The synthesis of quinolines via denitrogenative palladium-catalyzed cascade reaction of o-aminocinnamonitriles with arylhydrazines

Abstract

The first example of the palladium-catalyzed cascade reaction of o-aminocinnamonitriles with arylhydrazines has been achieved, providing an efficient synthetic pathway to access quinolines with moderate to good yields. Preliminary mechanistic experiments indicate that this cascade process involves sequential denitrogenative addition followed by an intramolecular cyclization.

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Introduction

Quinoline derivatives have become increasingly popular in the past few years due to their ubiquity in natural products, bioactive compounds, and other functional molecules. For example, quinoline scaffolds are privileged structures in medicinal chemistry, and therapeutic agents with such cores on the market or in clinical trials for the treatment of urological malignancies such as renal cell carcinoma (e.g., lenvatinib,¹ cabozantinib²) and the treatment of head and neck cancer (e.g., camptothecin³) (Fig. 1). Therefore, the development of the effective methods for the synthesis of quinolines has been actively pursued during the past several decades.⁴ However, less attention has been paid to the preparation of quinolines from nitriles.

Fig. 1 Representative bioactive quinoline derivatives.

Nitriles are well-known as solvents or ligands in organometallic reactions because of the inherently inert nature of the C≡N bond.⁵ For example, acetonitrile or benzonitrile are usually used as solvents or ligands in many transition-metal-catalyzed reactions.⁶ The development of transition-metal-catalyzed inert C≡N bond activation and further transformation has received significant attention from organic chemists because nitriles are normally very stable and abundant and cheap feedstock chemicals. Substantial progress towards this goal made in recent years, the transition-metal-catalyzed transformation of nitriles offers an attractive route for the synthesis of arylketones or further cyclization products by several other groups.⁷ Our group also developed transition-metal-catalyzed a series of tandem addition/cyclization reaction of nitriles with organoboron reagents for the synthesis of structurally diverse 5-membered, 6-membered, and 7-membered N-heterocycles.⁸ In addition, arylhydrazines are used as an important class of molecular building blocks in both synthetic and medicinal chemistry for preparing various nitrogen-containing compounds because of their high reactivity, low cost, and ready availability.⁹ Recent progresses in the development of using arylhydrazines as aryl source by denitrogenation have been documented.¹⁰ Despite the remarkable advances in transition-metal-catalyzed addition reactions of nitriles with arylating reagents into a valuable array of products to date, less attention has been paid to the using arylhydrazines as aryl sources by denitrogenation presumably due to the high dissociation energy from direct activation of the C–N bond.¹¹ To our knowledge, only two examples of denitrogenative palladium-catalyzed reaction of nitriles with arylhydrazines for the synthesis of aryl ketones have been reported (Scheme 1a).¹²

Scheme 1 Design of new approach to quinolines.

We envisioned that a Pd-catalyzed sequential denitrogenative addition followed by an intramolecular dehydrative cyclization of readily available o-aminocinnamonitriles with arylhydrazines would result in a tandem procedure for the preparation of 2-arylquinolines (Scheme 1b). It is worth noting that the amino group cannot approach the carbonyl group to achieve the intramolecular cyclization because of the steric configuration. Recently, Cheon group developed the synthesis of 2-substituted quinolines by the dehydrative cyclization of 2-aminostyryl ketones.¹³ These strategies involve the change of unreactive (E)-2-aminostyryl ketones into the unstable but reactive Z-configuration intermediate to undergo dehydrative cyclization reaction by using iodide^13a or benzylamine^13b as the nucleophilic catalyst. Recently, we reported the Pd-catalyzed tandem reaction of 2-aminostyryl nitriles with arylboronic acids for the synthesis of 2-arylquinolines.¹⁴ As part of the continuing efforts in our laboratory toward the development of novel transformations of nitriles,^8,14 we herein report the first example of the denitrogenative Pd-catalyzed cascade reaction of o-aminocinnamonitriles with arylhydrazines to afford 2-arylquinolines (Scheme 1b).

Results and discussion

We begin our investigation with readily available (E)-3-(2-aminophenyl)but-2-enenitrile (1a) and phenylhydrazine (2a) for the optimization of reaction conditions (Table 1).

Table 1 Optimization of reaction conditions^a

Entry	[Pd]	Ligand	Additive	Solvent	Yield^b (%)
a Conditions: 1a (0.3 mmol), 2a (0.6 mmol), Pd catalyst (10 mol%), ligand (20 mol%), additive (2 equiv.), solvent (2 mL), 90 °C, 24 h, air.b Isolated yield.c Under O2.
1	Pd(PPh3)4	L1	TFA	THF	0
2	Pd(OM)2	L1	TFA	THF	12
3	Pd(CF3CO2)2	L1	TFA	THF	19
4	Pd(PPh3)2Cl2	L1	TFA	THF	17
5	PdCl2	L1	TFA	THF	31
6	Pd2(dba)3	L1	TFA	THF	21
7	Pd(acac)2	L1	TFA	THF	23
8	PdCl2	L1	TFA	2-MeTHF	37
9	PdCl2	L1	TFA	DMF	41
10	PdCl2	L1	TFA	DMA	47
11	PdCl2	L1	TFA	1,4-Dioxane	23
12	PdCl2	L1	TFA	Toluene	56
13	PdCl2	L1	TFA	H2O	18
14	PdCl2	L2	TFA	Toluene	53
15	PdCl2	L3	TFA	Toluene	51
16	PdCl2	L4	TFA	Toluene	Trace
17	PdCl2	L5	TFA	Toluene	Trace
18	PdCl2	L6	TFA	Toluene	41
19	PdCl2	L7	TFA	Toluene	51
20	PdCl2	L1	AcOH	Toluene	Trace
21	PdCl2	L1	TsOH·H2O	Toluene	33
22	PdCl2	L1	MsOH	Toluene	21
23	PdCl2	L1	TfOH	Toluene	79(81)^c
24		L1	TfOH	Toluene	0
25	PdC12		TfOH	Toluene	0

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We initially found that the desired product 2-phenylquinoline (3a) could be obtained in 12% yield under the combination of Pd(OAc)₂, trifluoroacetic acid (TFA) and 2,2′-bipyridine (L1) in THF under air atmosphere (entry 2). Various palladium catalysts were tested (entries 3–7) and PdCl₂ exhibited the highest catalytic reactivity in 31% yield (entry 5). Delightedly, the yield of 3a could be improved to 56% using toluene as the solvent. Other solvents, including DMF, dimethylacetamide (DMA), 1,4-dioxane and H₂O were less efficient (entries 8–13). Replacement of L1 with other bidentate N-ligands (entries 13–19), resulted in lower yields. However, trace amounts of 3a was detected when sterically hindered ligands, such as 6,6′-dimethyl-2,2′-bipyridine (L4) and 2,9-dimethyl-1,10-phenanthroline (L5) were used (entries 16–17). An investigation of the effect of additive revealed that the yield of 3a was greatly increased to 81% under O₂ atmosphere (entry 23). The product 3a was not observed if either Pd catalyst or ligand was absent (entries 24 and 25).

Having the optimized reaction conditions in hand, we examined the substrates scope of this cascade reaction. First, the cascade reaction of (E)-3-(2-aminophenyl)but-2-enenitrile (1a) with different arylhydrazines were evaluated under optimized conditions (Table 2). The reactivities of para-, meta-, and ortho-tolylhydrazine were evaluated, and the results demonstrated that the steric effect of the substituent had an obvious impact on the reaction. For example, the reactions of 1a with para- and meta-tolylhydrazine afforded 85% and 79% yields of 3b and 3c, respectively, while the ortho-tolylhydrazine gave the desired product 3d with a diminished yield of 52%. Moderately electron-withdrawing halogens, such as fluoro (3e–3f), chloro (3g), and bromo (3h) groups, were compatible with this reaction, providing 42–76% yields. The substrate bearing a strong electron-withdrawing group (e.g., CF₃) could also be well tolerated, albeit giving the desired 3i in a slightly lower yield.

Table 2 Denitrogenative Pd-catalyzed cascade reaction of 1a with arylhydrazines^a

a Conditions: 1a (0.3 mmol), 2 (0.6 mmol), PdCl₂ (10 mol%), L1 (20 mol%), toluene (2 mL), TfOH (2 equiv.), 90 °C, 24 h, O₂, isolated yield.

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We next turned our attention to the effect of the reactions between substituted o-aminocinnamonitriles (1) and phenylhydrazine (2a) under standard conditions (Table 3). First, the influence of a variety of functional groups (R¹) on the phenyl ring of the 2-(benzylideneamino)benzonitriles was evaluated. Both electron-donating groups, such as methyl (3j) and methoxy (3k) moieties, and electron-withdrawing groups, such as fluoro (3l–3m), chloro (3n–3p) and bromo (3q) moieties, were also compatible, affording the corresponding desired products with moderate to good yields. Treatment of a strong electron-withdrawing trifluoromethyl substituent with 2a delivered product 3r in 36% yield. Finally, several representative examples of substituents (R²) on the carbon–carbon double bond were investigated. The R²-substituted products 3t, 3u and 3u was obtained in 71%, 62% and 57% yields, respectively, compared to relatively low yield of the product 3s in 51% yield. It is worth noting that the presence of the halogen in the products (e.g., 3h, 3q) is very useful for further synthetic elaborations by cross-coupling reaction thereby broadening the diversity of the products.

Table 3 Denitrogenative Pd-catalyzed reaction of o-aminocinnamonitriles with arylhydrazines^a

a Conditions: 1 (0.3 mmol), 2 (0.6 mmol), PdCl₂ (10 mol%), L1 (20 mol%), toluene (2 mL), TfOH (2 equiv.), 90 °C, 24 h, O₂, isolated yield.

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To gain insight into the mechanism of this cascade reaction, several control experiments were conducted (Scheme 2). The desired product 3a was not detected when the reaction was performed under N₂ atmosphere (Scheme 2a), which revealed that the reaction required the presence of oxygen. As expected, the reactions of (E)-3-(2-aminophenyl)-1-phenylprop-2-en-1-one (4a) under optimized conditions in the absence of phenylhydrazine achieved the product 2-phenylquinoline (3r) in 72% yield, indicating that 4a was proposed as a possible intermediate for this transformation (Scheme 2b). The cyclization of 4a gave the desired product 3r in 65% yield in the absence of TfOH (Scheme 2c). The cyclization of 4a could also proceed to afford 3r in 63% yield in the absence of PdCl₂/L1 (Scheme 2d). However, we attempted to perform the reaction in the absence of palladium catalyst and additive failed to give 3r (Scheme 2e).

Scheme 2 Control experiments.

On the basis of the above experimental results and previous reports,^12a a possible reaction mechanism for the formation of quinolines is shown in Scheme 3. The first step may involve metathesis between the palladium catalyst and arylhydrazide to form the palladiaziridine intermediate A, which is followed by the coordination of cyano group affording intermediate B. Oxidative addition of the intermediate B to palladium(0) species to give the corresponding two palladium(II) centered intermediate C via C–N bond cleavage. Thereafter, cracking of the intermediate C gives the intermediate D and the palladiaziridine intermediate E, which would be decomposed into palladium(0), N₂ and H₂O in the presence of oxygen. Then, carbopalladation of the cyano group affords the imine-Pd intermediate F. Protonation of F by TfOH gives the imine intermediate G and regenerates palladium(II) species. Hydrolysis of G under acidic conditions would deliver the ketone intermediate H. Finally, the ketone intermediate H undergoes C–C bond E/Z configurational tautomerization to give I in the presence of TfOH and/or palladium(II) species, which is followed by intramolecular cyclization to generate the desired quinolines 3.

Scheme 3 Plausible reaction mechanism for the formation of quinolines.

Conclusions

In summary, we have developed a new and complementary strategy for the synthesis of 2-arylquinolines in moderate to good yields by palladium-catalyzed cascade denitrogenative addition and intramolecular cyclization of o-aminocinnamonitriles with arylhydrazines.

Experimental section

General methods

Melting points are uncorrected. ¹H NMR and ¹³C NMR spectra were measured on a 500 MHz spectrometer using CDCl₃ as the solvent with tetramethylsilane (TMS) as an internal standard at room temperature. Chemical shifts are given n δ relative to TMS, and the coupling constants J are given in hertz. The starting materials o-aminocinnamonitriles¹⁵ and 4a¹⁶ were synthesized according to the method described in the literatures. Column chromatography was performed using EM silica gel 60 (300–400 mesh).

General procedure for the synthesis of quinolines

Under O₂ atmosphere, a Teflon-valve-sealed Schlenk tube was charged with o-aminocinnamonitriles and arylhydrazines, PdCl₂, L1, TfOH and toluene at room temperature. The reaction mixture was stirred for 10 minutes at room temperature for proper mixing of the reactants, and then heated at 90 °C (oil bath) with vigorous stirring for 24 hours. After the reaction equilibrium, the mixture was poured into ethyl acetate, which was washed with saturated NaHCO₃ (2 × 10 mL) and then brine (10 mL). The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under vacuum. The residue was purified by flash column chromatography (hexane/ethyl acetate) to afford the desired products.

4-Methyl-2-phenylquinoline (3a)¹⁷. White solid (53.2 mg, 81%), mp 62–63 °C. ¹H-NMR (500 MHz, CDCl₃) δ 8.22 (d, J = 10.5 Hz, 1H), 8.19–8.17 (m, 2H), 7.97 (d, J = 10.5 Hz, 1H), 7.75–7.70 (m, 2H), 7.56–7.52 (m, 3H), 7.49–7.46 (m, 1H), 2.73 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ 157.0, 148.2, 144.8, 139.8, 130.3, 129.3, 129.2, 128.8, 127.6, 127.3, 126.0, 123.6, 119.7, 19.0.

4-Methyl-2-(p-tolyl)quinoline (3b)¹⁸. Yellow oil (59.4 mg, 85%). ¹H-NMR (500 MHz, CDCl₃) δ 8.20 (d, J = 10.5 Hz, 1H), 8.09–8.07 (m, 2H), 7.98 (d, J = 10.0 Hz, 1H), 7.74–7.70 (m, 2H), 7.55–7.51 (m, 1H), 7.34 (d, J = 10.0 Hz, 2H), 2.74 (s, 3H), 2.45 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ 157.0, 148.1, 144.7, 139.3, 136.9, 130.2, 129.5, 129.3, 127.4, 127.2, 125.9, 123.6, 119.6, 21.3, 19.0.

4-Methyl-2-(m-tolyl)quinoline (3c)¹⁸. Yellow oil (55.2 mg, 79%). ¹H-NMR (500 MHz, CDCl₃) δ 8.22 (d, J = 8.0 Hz, 1H), 8.02–7.98 (m, 2H), 7.94 (d, J = 8.0 Hz, 1H), 7.74–7.70 (m, 2H), 7.56–7.52 (m, 1H), 7.44–7.41 (m, 1H), 7.29 (d, J = 7.5 Hz, 1H), 2.75 (s, 3H), 2.50 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ 157.3, 148.1, 144.7, 139.8, 138.4, 130.3, 130.0, 129.3, 128.7, 128.3, 127.3, 126.0, 124.7, 123.6, 119.9, 21.6, 19.0.

4-Methyl-2-(o-tolyl)quinoline (3d)¹⁹. Yellow oil (36.3 mg, 52%). ¹H NMR (500 MHz, CDCl₃) δ 8.20 (d, J = 8.5 Hz, 1H), 8.04–8.03 (m, 1H), 7.76–7.73 (m, 1H), 7.60–7.57 (m, 1H), 7.51–7.49 (m, 1H), 7.39 (s, 1H), 7.37–7.31 (m, 3H), 2.76 (s, 3H), 2.43 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ 160.3, 147.9, 144.3, 140.5, 136.0, 130.3, 130.0, 129.6, 129.3, 128.3, 126.0, 123.6, 123.1, 20.3, 18.8.

2-(4-Fluorophenyl)-4-methylquinoline (3e)²⁰. Yellow oil (54.1 mg, 76%). ¹H-NMR (500 MHz, CDCl₃) δ 8.18 (d, J = 10.5 Hz, 1H), 7.99 (d, J = 10.5 Hz, 1H), 7.92–7.90 (m, 2H), 7.75–7.71 (m, 1H), 7.67 (s, 1H), 7.58–7.54 (m, 1H), 7.50–7.45 (m, 1H), 7.17–7.13 (m, 1H), 2.76 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ 163.8 (d, J = 247.5 Hz), 155.9, 148.1, 145.0, 135.9 (d, J = 2.5 Hz), 130.2, 129.4, 129.3 (d, J = 7.5 Hz), 127.2, 126.1, 123.6, 119.4, 115.7 (d, J = 22.5 Hz), 19.0.

2-(3-Fluorophenyl)-4-methylquinoline (3f)²¹. Yellow oil (44.8 mg, 63%). ¹H-NMR (500 MHz, CDCl₃) δ 8.18 (m, 3H), 7.86–7.85 (m, 1H), 7.61–7.50 (m, 2H), 7.43–7.42 (m, 1H), 7.09–7.07 (m, 2H), 2.62 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ 163.4 (d, J = 243.8 Hz), 155.5 (d, J = 2.5 Hz), 148.0, 145.1, 142.1 (d, J = 7.5 Hz), 130.4, 130.2 (d, J = 8.8 Hz), 129.5, 127.4, 126.4, 123.6, 123.0 (d, J = 3.8 Hz), 119.4, 116.0 (d, J = 21.3 Hz), 114.4 (d, J = 22.5 Hz), 19.0.

2-(4-Chlorophenyl)-4-methylquinoline (3g)²². White solid (38.8 mg, 51%), mp 73–74 °C. ¹H-NMR (500 MHz, CDCl₃) δ 8.16 (d, J = 10.5 Hz, 1H), 8.11–8.09 (m, 2H), 7.98 (d, J = 10.5 Hz, 1H), 7.74–7.70 (m, 1H), 7.65 (s, 1H), 7.57–7.53 (m, 1H), 7.49–7.47 (m, 2H), 2.74 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ 155.5, 147.9, 144.9, 138.0, 135.3, 130.1, 129.4, 128.8, 128.6, 126.2, 126.1, 123.5, 119.1, 18.8.

2-(4-Bromophenyl)-4-methylquinoline (3h)²¹. White solid (37.5 mg, 42%), mp 66–67 °C. ¹H-NMR (500 MHz, CDCl₃) δ 8.22–8.15 (m, 2H), 8.05–8.03 (m, 1H), 8.00–7.98 (m, 1H), 7.74–7.71 (m, 1H), 7.66–7.63 (m, 2H), 7.57–7.51 (m, 2H), 2.77–2.76 (m, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ 155.3, 148.0, 145.2, 141.8, 132.1, 130.6, 130.4, 130.3, 129.6, 127.4, 126.4, 126.1, 123.7, 123.1, 119.5, 19.0.

4-Methyl-2-(4-(trifluoromethyl)phenyl)quinoline (3i)²³. Yellow oil (22.4 mg, 26%). ¹H-NMR (500 MHz, CDCl₃) δ 8.27 (d, J = 8.0 Hz, 2H), 8.20 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.78–7.24 (m, 4H), 7.60–7.57 (m, 1H), 2.79 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ 155.5, 148.0, 145.5, 143.0, 131.0 (d, J = 32.5 Hz), 130.4, 129.7, 127.9, 127.5, 126.6, 125.7 (q, J = 3.8 Hz), 124.2 (d, J = 270.0 Hz), 123.7, 119.6, 19.0.

6-Methyl-2-phenylquinoline (3j)²⁴. White solid (42.7 mg, 65%), mp 68–69 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.18–8.16 (m, 2H), 8.10 (d, J = 11.0 Hz, 2H), 7.82 (d, J = 11.0 Hz, 1H), 7.57–7.52 (m, 4H), 7.48–7.45 (m, 1H), 2.55 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ 156.5, 146.8, 139.8, 136.2, 136.1, 132.0, 129.4, 129.2, 128.8, 127.5, 127.2, 126.3, 119.0, 21.6.

6-Methoxy-2-phenylquinoline (3k)²⁵. White solid (36.7 mg, 52%), mp 125–126 °C. ¹H-NMR (500 MHz, CDCl₃) δ 8.15–8.14 (m, 1H), 8.13 (s, 1H), 8.11 (d, J = 6.0 Hz, 1H), 8.08 (d, J = 6.0 Hz, 1H), 7.83 (d, J = 11.5 Hz, 1H), 7.52 (dd, J₁ = 9.5 Hz, J₂ = 9.0 Hz, 2H), 7.45 (d, J = 9.5 Hz, 1H), 7.39 (dd, J₁ = 3.5 Hz, J₂ = 11.5 Hz, 1H), 7.08 (d, J = 3.5 Hz, 1H), 3.94 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ 157.8, 155.0, 144.4, 139.8, 135.5, 131.2, 128.9, 128.8, 128.2, 127.3, 122.3, 119.2, 105.1, 55.5.

6-Fluoro-2-phenylquinoline (3l)¹⁶. White solid (41.5 mg, 62%), mp 94–95 °C. ¹H-NMR (500 MHz, CDCl₃) δ 8.21–8.19 (m, 2H), 8.17–8.15 (m, 2H), 7.91 (d, J = 10.5 Hz, 1H), 7.56–7.44 (m, 5H); ¹³C-NMR (125 MHz, CDCl₃) δ 160.4 (d, J = 248.0 Hz), 156.7 (d, J = 2.8 Hz), 145.3, 139.2, 136.2 (d, J = 5.2 Hz), 132.1 (d, J = 9.1 Hz), 129.5, 128.9, 127.7 (d, J = 10.0 Hz), 127.5, 119.9 (d, J = 25.7 Hz), 119.7, 110.5 (d, J = 21.7 Hz).

7-Fluoro-2-phenylquinoline (3m)²⁵. White solid (38.8 mg, 58%), mp 88–89 °C. ¹H-NMR (500 MHz, CDCl₃) δ 8.22 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 7.5 Hz, 2H), 7.86–7.80 (m, 3H), 7.56–7.53 (m, 2H), 7.50–7.47 (m, 1H), 7.34–7.30 (m, 1H); ¹³C-NMR (125 MHz, CDCl₃) δ 163.3 (d, J = 249.6 Hz), 158.3, 149.3 (d, J = 12.9 Hz), 139.3, 136.6, 129.6, 129.4 (d, J = 10.0 Hz), 128.9, 127.6, 124.2, 118.3 (d, J = 2.5 Hz), 116.7 (d, J = 25.5 Hz), 113.3 (d, J = 20.2 Hz).

6-Chloro-2-phenylquinoline (3n)²⁶. White solid (40.3 mg, 56%), mp 109–110 °C. ¹¹H-NMR (500 MHz, CDCl₃) δ 8.16–8.11 (m, 4H), 7.89 (d, J = 9.0 Hz, 1H), 7.84–7.80 (m, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.55–7.52 (m, 2H), 7.49–7.47 (m, 1H); ¹³C-NMR (125 MHz, CDCl₃) δ 157.5, 146.6, 139.2, 135.8, 132.0, 131.3, 130.6, 129.6, 128.9, 127.7, 127.5, 126.1, 119.8.

6-Chloro-2-(p-methoxyphenyl)quinoline (3o)²⁷. Pale yellow solid (18.6 mg, 23%), mp 156–158 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.14 (d, J = 8.5 Hz, 2H), 8.08 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 3.89 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 161.1, 157.1, 146.6, 135.7, 131.5, 131.0, 130.5, 128.9, 127.5, 126.1, 119.3, 114.3, 55.4.

7-Chloro-2-phenylquinoline (3p)²⁸. White solid (38.8 mg, 54%), mp 106–107 °C. ¹H-NMR (500 MHz, CDCl₃) δ 8.21–8.15 (m, 4H), 7.89–7.87 (m, 1H), 7.77–7.75 (m, 1H), 7.56–7.48 (m, 4H); ¹³C-NMR (125 MHz, CDCl₃) δ 158.2, 148.5, 139.0, 136.7, 135.6, 129.7, 128.9, 128.7, 128.6, 127.6, 127.4, 125.5, 119.2.

6-Bromo-2-phenylquinoline (3q)²⁷. White solid (34.9 mg, 41%), mp 113–114 °C. ¹H-NMR (500 MHz, CDCl₃) δ 8.15 (d, J = 8.0 Hz, 2H), 8.10–8.09 (m, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.88–7.86 (m, 1H), 7.79–7.77 (m, 1H), 7.55–7.52 (m, 2H), 7.50–7.47 (m, 1H); ¹³C-NMR (125 MHz, CDCl₃) δ 157.6, 146.8, 139.1, 135.8, 133.1, 131.4, 129.6, 129.5, 128.9, 128.2, 127.5, 120.0, 119.7.

2-Phenyl-6-(trifluoromethyl)quinoline (3r)²⁹. White solid (29.5 mg, 36%), mp 118–119 °C. ¹H-NMR (500 MHz, CDCl₃) δ 8.26 (d, J = 10.0 Hz, 2H), 8.20–8.17 (m, 2H), 8.12 (s, 1H), 7.94 (d, J = 10.0 Hz, 1H), 7.90–7.88 (m, 1H), 7.58–7.51 (m, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ 159.3, 149.3, 138.9, 137.4, 130.9, 130.0, 129.0, 128.2, 127.9, 127.7, 126.1, 125.4 (q, J = 3.8 Hz), 125.3 (q, J = 3.8 Hz), 123.1, 120.0.

2-Phenylquinoline (3s)³⁰. White solid (31.4 mg, 51%), mp 84–85 °C. ¹H-NMR (500 MHz, CDCl₃) δ 8.24–8.17 (m, 4H), 7.89 (d, J = 10.0 Hz, 1H), 7.84 (d, J = 10.0 Hz, 1H), 7.76–7.72 (m, 1H), 7.56–7.52 (m, 3H), 7.49–7.46 (m, 1H); ¹³C-NMR (125 MHz, CDCl₃) δ 157.4, 148.3, 139.6, 136.8, 129.7, 129.6, 129.4, 128.8, 127.6, 127.4, 127.2, 126.3, 119.0.

4-Ethyl-2-phenylquinoline (3t)²⁰. Yellow oil (49.6 mg, 71%). ¹H-NMR (500 MHz, CDCl₃) δ 8.22 (d, J = 10.5 Hz, 1H), 8.18–8.17 (m, 2H), 8.04 (d, J = 10.5 Hz, 1H), 7.74–7.70 (m, 2H), 7.56–7.52 (m, 3H), 7.49–7.46 (m, 1H), 3.17 (q, J = 9.5 Hz, 2H), 1.45 (t, J = 9.5 Hz, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ 157.3, 150.4, 148.5, 140.1, 130.6, 129.2, 128.8, 127.6, 126.4, 126.0, 123.2, 117.8, 25.4, 14.2.

4-Isopropyl-2-phenylquinoline (3u)³¹. Yellow oil (45.9 mg, 62%). ¹H-NMR (500 MHz, CDCl₃) δ 8.21 (d, J = 10.5 Hz, 1H), 8.17–8.15 (m, 2H), 8.11 (d, J = 10.5 Hz, 1H), 7.79 (s, 1H), 7.73–7.70 (m, 1H), 7.57–7.52 (m, 3H), 7.49–7.45 (m, 1H), 3.84–3.77 (m, 1H), 1.48 (d, J = 9.0 Hz, 6H); ¹³C-NMR (125 MHz, CDCl₃) δ 157.4, 154.9, 148.6, 140.3, 130.7, 129.1, 129.0, 128.8, 127.6, 125.9, 125.8, 122.9, 114.9, 28.6, 23.0.

2,4-Diphenylquinoline (3v)³². White solid (48.1 mg, 57%), mp 104–105 °C. ¹H-NMR (500 MHz, CDCl₃) δ 8.28 (d, J = 10.5 Hz, 1H), 8.21–8.19 (m, 2H), 7.92 (d, J = 10.5 Hz, 1H), 7.83 (s, 1H), 7.77–7.73 (m, 1H), 7.57–7.55 (m, 4H), 7.54–7.48 (m, 5H); ¹³C-NMR (125 MHz, CDCl₃) δ 156.9, 149.4, 148.7, 139.6, 138.4, 130.0, 129.6, 129.4, 128.8, 128.6, 128.4, 127.6, 126.4, 125.8, 125.7, 119.4.

Conflicts of interest

There are no conflicts of interest to declare.

Acknowledgements

We thank the National Natural Science Foundation of China (No. 21572162) and the Natural Science Foundation of Zhejiang Province (No. LY20B020015) for financial support.

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra for products. See DOI: 10.1039/d0ra01043j

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