Preparation and Reactivity of 3-Amino-2,4-dichloroquinoline

Abstract

A simple and efficient synthesis of 2-substituted 3-amino-4-chloroquinolines and 2,4-disubstituted 3-aminoquinolines was carried out by reacting 3-amino-2,4-dichloroquinoline with various oxygen-, sulfur- and nitrogen-containing nucleophiles.

Key words

heterocycles - quinolones - dichloroquinoline - aminoquinoline - substitution

• References and Notes

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• 10 Preparation of 1-(2,4-Dichloroquinolin-3-yl)pyridinium Salt (5): Compound 4 (20 g, 83.6 mmol) and N,N-dimethylaniline (1.26 g, 10.4 mmol) were mixed and phosphorus oxychloride (200 mL, 2.14 mol) was added all at once. The reaction mixture was stirred vigorously and heated. Compound 4 gradually dissolved yielding a yellow solution that was heated to boiling for 3 h. The end of the reaction was determined using TLC. After the reaction was complete, the phosphorus oxychloride was removed by distillation under reduced pressure, and the crude product was mixed with toluene (2 × 40 mL). Toluene was properly removed by distillation under reduced pressure. Compound 5 was isolated in the form of a brown gel, which immediately solidified to form a brown resin. 1H NMR (400 MHz, DMSO-d6): δ = 9.53 (dd, 2 H, J = 6.7, 1.3 Hz, py), 9.10 (tt, 1 H, J = 7.9, 1.4 Hz, py), 8.63 (dd, 2 H, J = 7.9, 6.8 Hz, py), 8.40 (ddd, 1 H, J = 8.4, 1.3, 0.6 Hz, H-5), 8.28 (ddd, 1 H, J = 8.5, 1.2, 0.6 Hz, H-8), 8.19 (ddd, 1 H, J = 8.4, 7.0, 1.4 Hz, H-7), 8.03 (ddd, 1 H, J = 8.3, 7.0, 1.3 Hz, H-6). 13C NMR (100 MHz, DMSO-d6): δ = 150.6, 147.4, 147.3, 144.5, 141.7, 134.9, 131.8, 130.9, 125.8, 124.9, 130.1, 129.3.�
• 11 Procedure for the Preparation of 3-Amino-2,4-dichloroquinoline (3): Crude product 5 isolated in the previous reaction step was dissolved in EtOH (600 mL). The solution was heated to boiling, and ethanolamine (40 g, 0.65 mol) was added over a period of 20 min. The reaction mixture changed color from yellow to purple. The reaction mixture was heated to boiling for 16 h with vigorous stirring. During this time, another portion of ethanolamine (40 g, 0.65 mol) was added in small parts to the reaction mixture to bring the pH of the solution into the alkaline range (the fumes evolving from the reaction mixture must give a blue color on moistened pH paper). It is necessary to note that the amount of ethanolamine used for this reaction step and the reaction time depends on the quality of the phosphorus oxychloride removal in the previous step. The end of the reaction was determined using TLC and HPLC. EtOH was removed by distillation under reduced pressure. To a sufficiently concentrated reaction mixture (170 g), H₂O was added, and compound 3 solidified in the form of a white solid. The product was washed with H₂O and dried (8.4 g; 47% yield calculated on compound 4). Note: Ethylamine and aq methylamine were both successfully used for this reaction instead of ethanolamine. When using these compounds, the reactions were carried out in pressure tubes; C₉H₆Cl₂N₂ (211.99); mp 115–119 °C. MS: m/z (%) = 213.2 (100) [M(³⁵Cl) + H]⁺, 215.2 (60), 217.1 (10). 1H NMR (400 MHz, DMSO-d6): δ = 7.90 (ddd, 1 H, J = 8.4, 1.4, 0.6 Hz, H-5), 7.82 (ddd, 1 H, J = 8.3, 1.2, 0.6 Hz, H-8), 7.62 (ddd, 1 H, J = 8.4, 6.9, 1.3 Hz, H-6), 7.52 (ddd, 1 H, J = 8.3, 6.9, 1.4 Hz, H-7), 6.13 (s, 2 H, NH2). 13C NMR (100 MHz, DMSO-d6): δ = 140.4, 139.6, 136.4, 128.8, 128.6, 126.7, 126.6, 122.1, 118.0. �
• 12 Procedure for the Preparation of 3-Amino-4-chloroquinolin-2(1H)-one (6): Compound 3 (0.4 g, 1.87 mmol) and ammonium acetate (3.45 g, 44.75 mmol) were mixed and the reaction mixture was stirred in an oil bath in the melted state (160 °C) for 6 h. The end of the reaction was determined using TLC. The reaction mixture was diluted with H₂O and extracted with EtOAc. The combined organic layer was dried and concentrated. A white crystalline powder was obtained with a yield of 0.1 g (yield: 28%); C₉H₇ClN₂O (194.02); mp 227–233 °C. MS: m/z (%) = 195.1 (100) [M(³⁵Cl) + H]⁺, 197.1 (35). 1H NMR (400 MHz, DMSO-d6): d = 12.1 (bs, 1 H, NH), 7.59 (dd, 1 H, J = 7.6, 1.0 Hz, H-5), 7.29-7.27 (m, 2 H, H-7, H-8), 7.22 (t, 1 H, J = 7.8 Hz, H-6), 5.76 (s, 2 H, NH2). 13C NMR (100 MHz, DMSO-d6): d = 157.0, 135.4, 131.3, 125.9, 123.1, 121.6, 119.8, 115.5, 111.1.�
• 13 Procedure for the Preparation of 5-Chlorotetrazolo[1,5-a]quinolin-4-amine (7): Compound 3 (1 g, 4.7 mmol) was dissolved in DMF (4.6 g). To this solution was added a suspension of sodium azide (0.5 g, 7.7 mmol) in DMF (15.8 g). The reaction mixture was stirred vigorously and heated to 100 °C for 5.5 h. During this time, another portion of DMF (10.5 g) was added. The end of the reaction was determined using TLC. DMF was removed by distillation under reduced pressure, and the reaction mixture was extracted with EtOAc. The organic layer was dried and concentrated. The product was obtained in the form of almost white powder (0.75 g, 73%); C₉H₆ClN₅ (219.03); mp 243–244 °C. MS: m/z (%) = 220.1 (100) [M(³⁵Cl) + H]⁺, 222.1 (30). 1H NMR (400 MHz, DMSO-d6): δ = 8.39 (dd, 1 H, J = 8.2, 1.0 Hz, H-8), 7.92 (dd, 1 H, J = 8.3, 1.0 Hz, H-5), 7.66 (ddd, 1 H, J = 8.4, 7.3, 1.3 Hz, H-6), 7.57 (ddd, 1 H, J = 8.4, 7.3, 1.3 Hz, H-7), 6.84 (s, 2 H, NH2). 13C NMR (100 MHz, DMSO-d6): δ = 143.6, 130.5, 129.1, 126.5, 124.6, 123.9, 123.3, 116.6, 106.4.���
• 14 Representative Procedure for the Preparation of 3-Amino-4-chloro-2-methoxyquinoline (8): Compound 3 (0.13 g, 0.61 mmol) was dissolved in hot MeOH (2 mL). Into this solution a solution of sodium methoxide (0.2 g, 3.7 mmol) in MeOH (4 mL) was added, and the reaction mixture was heated to boiling for 2 h. The end of the reaction was determined using TLC. The addition of H₂O to the reaction mixture led to the solidification of the product in the form of a white solid (yield: 0.11 g, 90%); C₁₀H₉ClN₂O (208.04); mp 89–92 °C. MS: m/z (%) = 208.9 (100) [M(³⁵Cl) + H]⁺, 210.9 (33). 1H NMR (400 MHz, DMSO-d6): δ = 7.78 (dd, 1 H, J = 7.6, 1.9 Hz, H-5), 7.68 (dd, 1 H, J = 7.5, 1.8 Hz, H-8), 7.43- 7.36 (m, 2 H, H-6, H-7), 5.72 (s, 2 H, NH2), 4.04 (s, 3 H, Me). 13C NMR (100 MHz, DMSO-d6): δ = 153.3, 138.2, 130.4, 127.1, 125.6, 125.6, 124.7, 121.4, 114.8, 54.3.�
• 15 Representative Procedure for the Preparation of 3-Amino-4-chloro-2-(4-methylphenoxy)quinoline (16): K₂CO₃ (1.29 g, 9.33 mmol) and 4-methylphenol (0.5 g, 4.62 mmol) were mixed with DMF (6 mL). Into this suspension a solution of compound 3 (0.5 g, 2.35 mmol) dissolved in DMF (5 mL) was added. The reaction mixture was heated to 120 °C for 4.5 h. The end of the reaction was determined using TLC. After the reaction was complete, the K₂CO₃ was filtered off, and the solution was concentrated under reduced pressure. The crude product was mixed with an aqueous solution of K₂CO₃ (10%) and extracted with Et₂O. The organic layers were separated and dried. The evaporation of Et₂O under reduced pressure and the addition of MeOH led to the solidification of the product in the form of a white powder (yield: 0.17 g, 25%); C₁₆H₁₃ClN₂O (284.07); mp 104–107 °C. MS: m/z (%) = 285.2 (100) [M(³⁵Cl) + H]⁺, 287.1 (32). 1H NMR (400 MHz, DMSO-d6): d = 7.82 (ddd, 1 H, J = 8.2, 1.4, 0.5 Hz, H-5), 7.47 (ddd, 1 H, J = 8.2, 1.3, 0.5 Hz, H-8), 7.45-7.30 (m, 2 H, H-6, H-7), 7.26 (dd, 2 H, J = 8.7, 0.6 Hz, ArH), 7.17 (d, 2 H, J = 8.5 Hz, ArH), 6.01 (s, 2 H, NH2), 2.35 (s, 3 H, Me). 13C NMR (100 MHz, DMSO-d6): d = 152.7, 151.3, 137.7, 134.5, 130.7, 130.3, 127.4, 126.2, 125.7, 125.2, 122.1, 121.4, 116.0, 20.9.�
• 16 Representative Procedure for the Preparation of 3-Amino-4-chloro-2-(4-chlorophenylthio)quinoline (23) and 3-Amino-2,4-bis(4-chlorophenylthio)quinoline (28): K₂CO₃ (1.29 g, 9.33 mmol) and 4-chlorothiophenol (0.67 g, 4.63 mmol) were mixed with DMF (6 mL). Into this suspension a solution of compound 3 (0.5 g, 2.35 mmol) dissolved in DMF (5 mL) was added. The reaction mixture was heated to 120 °C for 30 min. The end of the reaction was determined using TLC. After the reaction was complete, the K₂CO₃ was filtered off, and the solution was concentrated under reduced pressure. The crude product was mixed with H₂O and extracted with Et₂O. The organic layers were separated and dried. The Et₂O was removed by distillation under reduced pressure and the crude product was dissolved in toluene. Both of 4-chlorothiophenol derivatives (23, 28) (and the corresponding disulfide that was observed as a by-product) were separated using liquid column chromatog-raphy (stationary phase: silica gel; mobile phase: toluene). Compound 23: yield: 0.25 g, 33%; compound 28: yield: 0.25 g, 25%. Compound 23: C₁₅H₁₀Cl₂N₂S (319.99); mp 147–150 °C. MS: m/z (%) = 320.9 (100) [M(³⁵Cl) + H]⁺, 322.8 (65), 324.8 (15). 1H NMR (400 MHz, DMSO-d6): δ = 7.88 (dd, 1 H, J = 8.2, 1.3 Hz, H-5), 7.56 (d, 2 H, J = 8,6 Hz, ArH), 7.56–7.54 (m, 1 H, H- 8), 7.52 (d, 2 H, J = 8,6 Hz, ArH), 7.52–7.50 (m, 1 H, H- 6), 7.41 (dt, 1 H, J = 7.6, 1.2 Hz, H-7), 5.86 (s, 2 H, NH2). 13C NMR (100 MHz, DMSO-d6): δ = 148.0, 141.1, 136.8, 135.8, 134.0, 129.7, 129.4, 128.6, 127.9, 126.1, 125.9, 122.0, 117.2.� Compound 28: C₂₁H₁₄Cl₂N₂S₂ (427.99); mp 120–123 °C. MS: m/z (%) = 428.9 (100) [M(³⁵Cl) + H]⁺, 430.8 (70), 431.8 (25)1H NMR (400 MHz, DMSO-d6): d = 7.95 (dd, 1 H, J = 8.3, 0.8 Hz, H-5), 7.57 (d, 2 H, J = 8.8 Hz, ArH), 7.56– 7.53 (m, 1 H, H-8), 7.53 (d, 2 H, J = 8.7 Hz, ArH), 7.42 (dt, 1 H, J = 7.6, 1.2 Hz, H-6), 7.34 (dt, 1 H, J = 7.5, 1.3 Hz, H-7), 7.29 (d, 2 H, J = 8.6 Hz, ArH), 7.04 (d, 2 H, J = 8.6 Hz, ArH), 6.03 (s, 2 H, NH2). 13C NMR (100 MHz, DMSO-d6): d = 148.4, 143.0, 141.4, 135.9, 134.2, 134.0, 131.0, 129.7, 129.4, 129.4, 129.3, 128.9, 128.7, 128.0, 125.6, 123.7, 110.8�
• 17 Representative Procedure for the Preparation of N ²-Butyl-4-chloroquinoline-2,3-diamine (32): Compound 3 (0.5 g, 2.35 mmol) was dissolved in n-butylamine (6.8 g, 93 mmol). The reaction mixture was stirred and heated to boiling for 13 h. Then, the excess of n-butylamine was removed by distillation under reduced pressure. The addition of MeOH–H₂O (1:1) yielded the product in the form of a white solid (yield 0.5 g, 85%); C₁₃H₁₆ClN₃ (249.10); mp 59–62 °C. MS: m/z (%) = 250.1 (75) [M(³⁵Cl) + H]⁺, 252.1 (24) 1H NMR (400 MHz, DMSO-d6): δ = 8.46 (dd, 1 H, J = 8.2, 0.9 Hz, H-8), 7.64 (dd, 1 H, J = 8.1, 1.2 Hz, H-5), 7.26 (ddd, 1 H, J = 8.3, 7.0, 1.5 Hz, H-7), 7.18 (ddd, 1 H, J = 8.2, 7.0, 1.3 Hz, H-6), 6.60 (t, 1 H, J = 4.9 Hz, NH), 5.63 (s, 2 H, NH2), 3.49 (dt, 2 H, J = 7.0, 5.1 Hz, CH2), 1.63 (tt, 2 H, J = 11.1, 7.5 Hz, CH2), 1.41 (qt, 2 H, J = 14.4, 7.3 Hz, CH2), 0.94 (t, 3 H, J = 7.4 Hz, Me). 13C NMR (100 MHz, DMSO-d6): δ = 148.6, 141.1, 128.8, 125.8, 125.2, 122.5, 122.3, 121.2, 114.2, 41.3, 31.3, 20.3, 14.3