Subscribe to RSS
DOI: 10.1055/s-0029-1219818
Synthesis of 3-Chloro-4-fluoro-7,8-dihydro-6H-isoquinolin-5-one and Its Derivatives
Publication History
Publication Date:
13 April 2010 (online)
![](https://www.thieme-connect.de/media/synlett/201009/lookinside/thumbnails/10.1055-s-0029-1219818-1.jpg)
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
-
1a
Hagmann WK. J. Med. Chem. 2008, 51: 4359 -
1b
Purser S.Moore PR.Swallow S.Gouverneur V. Chem. Soc. Rev. 2008, 37: 320 -
1c
Kirk KL. J. Fluorine Chem. 2006, 127: 1013 -
1d
Isanbor C.O’Hagan D.
J. Fluorine Chem. 2006, 127: 303 -
1e
Böhm H.-J.Banner D.Bendels S.Kansy M.Kuhn B.Müller K.Obst-Sander U.Stahl M. ChemBioChem 2004, 5: 637 - 2
Olsen JA.Banner DW.Seiler P.Obst-Sander U.D’Arcy A.Stihle M.Müller K.Diederich F. Angew. Chem. Int. Ed. 2003, 42: 2507 -
3a
Morgenthaler M.Schweizer E.Hoffmann-Röder A.Benini F.Martin RE.Jaeschke G.Wagner B.Fischer H.Bendels S.Zimmerli D.Schneider J.Diederich F.Kansy M.Müller K. ChemMedChem 2007, 2: 1100 -
3b
Schlosser M. Angew. Chem. Int. Ed. 1998, 37: 1496 - 4
Bégué J.-P.Bonnet-Delpon D. ChemMedChem 2007, 2: 608 - 5
Barker AJ.Gibson KH.Grundy W.Godfrey AA.Barlow JJ.Healy MP.Woodburn JR.Ashton SE.Curry BJ.Scarlett L.Henthorn L.Richards L. Bioorg. Med. Chem. Lett. 2001, 11: 1911 -
6a
Lardenois P.Frost J.Dargazanli G.George P. Synth. Commun. 1996, 26: 2305 -
6b
Nicolaou KC.Baran PS.Zhong Y.-L. J. Am. Chem. Soc. 2001, 123: 3183 -
7a
Caprathe BW.Jaen JC.Wise LD.Heffner TG.Pugsley TA.Meltzer LT.Parvez M. J. Med. Chem. 1991, 34: 2736 -
7b
Chan L.Stefanac T.Turcotte N.Hu Z.Chen Y.Bédard J.May S.Jin H. Bioorg. Med. Chem. Lett. 2000, 10: 1477 -
7c
Hsin L.-W.Chang L.-T.Liou H.-L. Synlett 2008, 2299 -
8a
Kirk KL. Org. Process Res. Dev. 2008, 12: 305 -
8b
Singh RP.Shreeve JM. Acc. Chem. Res. 2004, 37: 31 -
8c
Watson DA.Su M.Teverovskiy G.Zhang Y.García-Fortanet J.Kinzel T.Buchwald SL. Science 2009, 325: 1661 -
9a
Schlosser M. Synlett 2007, 3076 -
9b
Gros P.Fort Y. Eur. J. Org. Chem. 2002, 3375 -
9c
Mongin F.Quéguiner G. Tetrahedron 2001, 57: 4059 -
9d
Marsais F.Queguiner G. Tetrahedron 1983, 39: 2009 -
10a
Deiters A.Martin SF. Chem. Rev. 2004, 104: 2199 -
10b
Schuster M.Blechert S. Angew. Chem. Int. Ed. Engl. 1997, 36: 2036 -
10c
Brown RCD.Satcharoen V. Heterocycles 2006, 70: 705 - Recent examples on ortho-fluoro lithiation, see:
-
11a
Humphries AC.Gancia E.Gilligan MT.Goodacre S.Hallett D.Merchant KJ.Thomas SR. Bioorg. Med. Chem. Lett. 2006, 16: 1518 -
11b
Bobbio C.Schlosser M.
J. Org. Chem. 2005, 70: 3039 -
11c
Marzi E.Bobbio C.Cottet F.Schlosser M. Eur. J. Org. Chem. 2005, 10: 2116 -
11d
Ondi L.Volle J.-N.Schlosser M. Tetrahedron 2005, 61: 717 - 12
Balasubramaniam S.Aidhen IS. Synthesis 2008, 3707 -
13a
Snieckus V. Chem. Rev. 1990, 90: 879 -
13b
Epsztajn J.JóŸwiak A.Szcześniak AK. Curr. Org. Chem. 2006, 10: 817 -
13c
Azzouz R.Bischoff L.Fruit C.Marsais F. Synlett 2006, 1908 -
14a
Townsend CA.Bloom LM. Tetrahedron Lett. 1981, 22: 3923 -
14b
Stagliano KW.Malinakova HC. Tetrahedron Lett. 1998, 39: 4941 -
15a
Comins DL. Synlett 1992, 615 -
15b
Comins DL.Baevsky MF.Hong H. J. Am. Chem. Soc. 1992, 114: 10971 -
15c
Josien H.Ko S.-B.Bom D.Curran DP. Chem. Eur. J. 1998, 4: 67 -
16a
Luo S.Fang F.Zhao M.Zhai H. Tetrahedron 2004, 60: 5353 -
16b
Bjoerk P.Aakermann T.Hoernfeldt A.-B.Gronowitz S. J. Heterocycl. Chem. 1995, 32: 751 -
19a
Uma R.Crévisy C.and Grée R. Chem. Rev. 2003, 103: 27 -
19b
Xu M.Vasella A. Helv. Chim. Acta 2006, 89: 1140 -
19c
Wang PX.White CR. WO 2005/047291 A1
References and Notes
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.
18Grubbs’ catalysts I and II and Grignard reagents were purchased from Aldrich Co. and used as obtained
20Characterization 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