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Synlett 2010(9): 1397-1401  
DOI: 10.1055/s-0029-1219818
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 3-Chloro-4-fluoro-7,8-dihydro-6H-isoquinolin-5-one and Its Derivatives

Juraj Velcicky*, Daniel Pflieger
Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland
Fax: +41(61)3248847; e-Mail: juraj.velcicky@novartis.com;
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Publication History

Received 23 January 2010
Publication Date:
13 April 2010 (online)

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Abstract

Synthesis of novel 3-chloro-4-fluoro-7,8-dihydro-6H-isoquinolin-5-one and its derivatives using sequential ortho-formylation/ortho-allylation reactions of 2-chloro-3-fluoropyridine and ring-closing metathesis is described.

Key words

ortho-lithiation - ring-closing metathesis - fluoro pyridine - isoquinolinone - fused-ring system

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17

Preparation of compound 15: t-BuLi (1.7 m in heptane, 14.1 mL, 24 mmol) was added within 15 min to a solution of 2-chloro-3-fluoropyridine (3 g, 22.8 mmol) in anhydrous THF (70 mL) at -78 ˚C. After stirring for 1 h at -78 ˚C, N-formyl-l-N,N′,N′-trimethylethylene-1,2-diamine (3.21 g, 24 mmol) was added slowly and the reaction mixture was left to warm to -40 ˚C, followed by addition of n-BuLi (1.6 m in hexane, 21.4 mL, 34.2 mmol). The red-brown solution was stirred for 3 h at -30 ˚C before CuBr (4.25 g, 29.6 mmol) was added. The reaction mixture was then allowed to reach 0 ˚C and was stirred at this temperature for 1 h. After cooling back to -30 ˚C, a solution of allylbromide (3.1 mL, 36.5 mmol) in anhydrous THF (50 mL) was added. After stirring for 1 h at -10 ˚C, the mixture was quenched by addition of sat. aq NH4Cl, filtered over Hyflo® and rinsed with diethyl ether. The organic layer was then washed with sat. aq NH4Cl and brine. After drying over Na2SO4 and filtration, the mixture was concentrated under vacuum. The crude mixture was further purified by gradient MPLC (ethyl acetate-cyclohexane, 5→15%), followed by a second MPLC (diethyl ether-cyclohexane, 10→15%) to provide the product 15 (1.85 g, 41%) as a yellow oil. Spectral data for compound 15: ¹H NMR (500 MHz, DMSO-d 6): δ = 10.31 (s, 1 H), 8.32 (s, 1 H), 5.97 (m, 1 H), 5.07 (dd, J = 10.2, 1.5 Hz, 1 H), 5.00 (dd, J = 17.2, 1.6 Hz, 1 H), 3.72 (d, J = 6.3 Hz, 2 H); ¹³C NMR (100 MHz, DMSO-d 6): δ = 187.6, 153.0 (d, J C,F = 268 Hz), 146.3 (d, J C,F = 7 Hz), 136.4 (d, J C,F = 20 Hz), 135.2, 128.8 (d, J C,F = 6 Hz), 116.6, 32.2; ESI-HRMS: m/z [M + H]+ calcd for C9H8ClFNO: 200.0278; found: 200.0274.

18

Grubbs’ catalysts I and II and Grignard reagents were purchased from Aldrich Co. and used as obtained

20

Characterization of final compounds. 5a: ¹H NMR (500 MHz, DMSO-d 6): δ = 8.40 (s, 1 H), 2.97 (t, J = 6.1 Hz, 2 H), 2.66 (t, J = 6.3 Hz, 2 H), 2.06 (m, 2 H); ¹³C NMR (100 MHz, DMSO-d 6): δ = 193.6, 150.5 (d, J C,F = 273 Hz), 145.1 (d, J C,F = 8 Hz), 139.5, 135.8 (d, J C,F = 20 Hz), 126.9, 39.3, 25.0, 21.5; ESI-HRMS: m/z [M + H]+ calcd for C9H8ClFNO: 200.0278; found: 200.0274; 5b: ¹H NMR (500 MHz, DMSO-d 6): δ = 8.38 (s, 1 H), 3.03 (m, 2 H), 2.77 (m, 1 H), 2.14 (m, 1 H), 1.84 (m, 2 H), 1.12 (d, J = 6.6 Hz, 3 H); ¹³C NMR (125 MHz, DMSO-d 6): δ = 197.1, 151.2 (d, J C,F = 274 Hz), 145.9 (d, J C,F = 8 Hz), 140.0, 136.4 (d, J C,F = 20 Hz), 127.5, 42.9, 29.8, 24.7, 14.8; ESI-HRMS: m/z [M + H]+ calcd for C10H9ClFNO: 214.0430; found: 214.0431; 5c: ¹H NMR (500 MHz, DMSO-d 6): δ = 8.26 (s, 1 H), 2.86 (m, 2 H), 2.75 (m, 2 H), 1.79 (m, 4 H); ¹³C NMR (125 MHz, DMSO-d 6): δ = 201.6, 149.4 (d, J C,F = 264 Hz), 145.1, 136.3 (d, J C,F = 20 Hz), 135.9 (d, J C,F = 11 Hz), 135.1, 41.5, 28.3, 24.7, 22.3; ESI-HRMS: m/z [M + H]+ calcd for C10H10ClFNO: 214.0430; found: 214.0430; 5d: ¹H NMR (500 MHz, DMSO-d 6): δ = 8.26 (s, 1 H), 2.91 (m, 1 H), 2.83 (m, 1 H), 2.71 (m, 1 H), 2.65 (m, 1 H), 2.02 (m, 1 H), 1.90 (m, 1 H), 1.48 (m, 1 H), 0.98 (d, J = 6.7 Hz, 3 H); ¹³C NMR (100 MHz, DMSO-d 6): δ = 198.9, 148.5 (d, J C,F = 263 Hz), 144.5 (d, J C,F = 6 Hz), 135.6, 135.5, 135.1, 49.2, 33.1, 30.1, 27.5, 21.3; ESI-HRMS: m/z [M + H]+ calcd for C11H12ClFNO: 228.0586; found: 228.0586