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Synlett 2006(1): 0065-0068  
DOI: 10.1055/s-2005-922790
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Jae Hak Leea, Byoung Se Leea, Hyunik Shinb, Do Hyun Namb, Dae Yoon Chi*a
a Department of Chemistry, Inha University, 253 Yonghyundong Namgu, Inchon 402-751, Korea
Fax: +82(32)8675604; e-Mail: dychi@inha.ac.kr;
b Chemical Development, LG Life Sciences, 104-1 Moonjidong, Yusunggu, Taejon 305-380, Korea
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Publication History

Received 24 September 2005
Publication Date:
16 December 2005 (online)

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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.

Key words

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

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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.