Acetonitrile-Mediated Synthesis of 2,4-Dichloroquinoline from 2-Ethynyl­aniline and 2,4-Dichloroquinazoline from Anthranilonitrile

Abstract

2,4-Dichloroquinolines and 2,4-dichloroquinazolines were synthesized from 2-ethynylanilines and anthranilonitriles, respectively, using diphosgene in acetonitrile and heating at 130 °C or 150 °C for 12 hours. This reaction was applied to the synthesis of 4,6-dichloropyrazolo[3,4-d]pyrimidine (dichloro-9H-isopurine). The postulated mechanism is also described.

2,4-dichloroquinoline - diphosgene - acetonitrile-mediated reaction - 2,4-dichloroquinazoline

References and Notes

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21

2-Ethynylanilines 2a-e; General Procedure. The mixture of N-trifluoro-2-iodoaniline (1.5 g, 4.76 mmol) and K₂CO₃ (1.97 g, 14.28 mmol) in 50 mL of MeOH-H₂O (10:1) was stirred at 50 °C for 24 h. H₂O (200 mL) was added and the product was extracted with EtOAc (3 × 50 mL), dried over Na₂SO₄, and concentrated in vacuo. The resulting iodoaniline (1.00 g, 4.56 mmol), TMSCºCH (0.968 mL, 6.85 mmol), PdCl₂(PPh₃)₂ (96.14 mg, 137 µmol), and CuI (26.08 mg, 137 µmol) were dissolved in THF (200 mL) at r.t. under a N₂ atmosphere. After 5 min, Et₃N (50 mL) was added dropwise and the solution was stirred at r.t. for 1 h. H₂O was added, the reaction mixture was extracted with EtOAc (3 × 50 mL), dried over Na₂SO₄, and concentrated in vacuo. The crude material was dissolved directly in anhyd THF (100 mL), and TBAF (1 M THF; 9.2 mL) was added dropwise at 0 °C to r.t. The reaction mixture was extracted with EtOAc (3 × 50 mL) and dried over Na₂SO₄. The residue was purified by flash column chromatography (10% EtOAc-hexane).
2-Ethynylaniline ( 2a) Yield: 90%; brown liquid. ¹H NMR (200 MHz, CDCl₃): δ = 7.32 (dd, J = 8.1, 1.5 Hz, 1 H), 7.15 (td, J = 7.7, 1.6 Hz, 1 H), 6.72-6.64 (m, 2 H), 4.24 (br s, 2 H), 3.39 (s, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 148.4, 132.5, 130.0, 117.7, 114.2, 106.5, 82.4, 80.6. MS (ESI): m/z (%) = 118.4 (M⁺ + H, 100), 91.5. HRMS (CI): m/z calcd for C₈H₈N (MH⁺): 118.0657; found: 118.0661.
2-Ethynyl-4-trifluoromethylaniline ( 2e) Yield: 90%; dark brown liquid. ¹H NMR (200 MHz, CDCl₃): δ = 7.57 (d, J = 1.8 Hz, 1 H), 7.35 (dd, J = 8.8, 1.8 Hz, 1 H), 6.71 (d, J = 8.8 Hz, 1 H), 4.59 (br s, 2 H), 3.42 (s, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 148.6, 145.1, 127.7 (q, J = 3.7 Hz), 124.7 (q, J = 3.6 Hz), 118.2 (q, J = 72.8 Hz), 111.4, 103.8, 81.2, 27.3. MS (ESI): m/z (%) = 166.4 (MH⁺, 100), 117.4. HRMS (CI): m/z calcd for C₉H₇F₃N (MH⁺): 186.0531; found: 186.0533.
2-Aminobenzonitrile 3b, 3d, 3e; General Procedure. Under a N₂ atmosphere N-trifluoroacetyl-4-chloro-2-iodoaniline (750 mg, 2.15 mmol) and CuCN (192.5 mg, 2.15 mmol) were dissolved in DMF (50 mL) at r.t., and then the reaction mixture was heated at 100 °C for 30 min. After cooling, the reaction mixture was poured into H₂O (300 mL). The product was extracted with EtOAc (3 × 100 mL), dried over Na₂SO₄, and concentrated in vacuo. The crude was added to a solution of K₂CO₃ (594 mg, 8.59 mmol) in MeOH-H₂O (10:1) and stirred at r.t. for 12 h. H₂O (200 mL) was added and the product was extracted with EtOAc (2 × 50 mL), dried over Na₂SO₄, and concentrated. The residue was purified by flash column chromatography (10% EtOAc-hexane). All 2-aminobenzonitriles gave satisfactory analytical data; both 3a and 3c are commercially available.
2-Amino-5-chlorobenzonitrile ( 3b) Yield: 84%; gray solid; mp 95.0-96.3 °C. ¹H NMR (200 MHz, CDCl₃): δ = 7.35 (d, J = 2.6 Hz, 1 H), 7.28 (dd, J = 9.0, 2.0 Hz, 1 H), 4.42 (br s, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 145.9, 131.9, 128.8, 119.9, 114.1, 113.9, 94.5. MS (EI): m/z (%) = 152.8 (M⁺). Anal. calcd for C₇H₅N₂Cl: C, 55.10; H, 3.30; N, 18.36. Found: C, 55.10; H, 3.44; N, 17.97.
2,4-Dichloroquinolines and 2,4-Dichloroquinazolines; Typical Procedure. To a solution of 2a (500 mg, 4.27 mmol) in CH₃CN (5 mL; dried over molecular sieves) was added diphosgene (0.781 mL, 6.35 mmol) at r.t. (white precipitate formed) under a N₂ atmosphere. The reaction mixture was placed in a tightly capped pressure tube, stirred at 130 °C for 12 h, and then cooled to r.t. H₂O was carefully added to the mixture and then allowed to stand for 30 min at r.t. The combined organic layers were washed with EtOAc (3 × 100 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography (10% EtOAc-hexane).
2,4-Dichloro-6-trifluoromethylquinoline ( 7e) Yield: 25%; white solid; mp 113.5-116.1 °C. ¹H NMR (200 MHz, CDCl₃): δ = 8.50 (d, J = 1.8 Hz, 1 H), 8.14 (d, J = 9.4 Hz, 1 H), 7.97 (dd, J = 8.8, 1.8 Hz, 1 H), 7.62 (s, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 152.3, 149.1, 145.1, 130.3, 129.5, 127.3 (q, J = 3.0 Hz), 123.4 (q, J = 84.9 Hz), 123.3, 122.2 (q, J = 4.5 Hz). MS (EI): m/z (%) = 269 (M⁺), 267 (M⁺), 265 (M⁺, 100), 230, 210, 194. HRMS (CI): m/z calcd for C₁₀H₅Cl₂F₃N (MH⁺): 265.9751; found: 265.9753.
2,4-Dichloro-6-trifluoromethylquinazoline ( 8g) Yield: 41%; white solid; mp 100.4-102.5 °C. ¹H NMR (200 MHz, CDCl₃): δ = 8.57 (s, 1 H), 8.17-8.16 (m, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 164.8, 157.2, 153.3, 131.7 (q, J = 3.1 Hz), 131.1 (q, J = 33.6 Hz), 129.4, 125.6, 123.9 (q, J = 4.4 Hz), 121.6. MS (ESI): m/z (%) = 271 (M⁺ + H), 269 (M⁺ + H), 267 (M⁺ + H), 249 (100), 229, 215, 195, 163, 123. HRMS (CI): m/z calcd for C₉H₄Cl₂F₃N₂ (MH⁺): 266.9704; found: 266.9700.