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Synlett 2011(2): 241-244  
DOI: 10.1055/s-0030-1259309
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

2-Substituted-2,3-dihydro-1H-quinolin-4-ones via Acid-Catalyzed Tandem Rupe Rearrangement-Donnelly-Farrell Ring Closure of 2-(3′-Hydroxy­propynyl)anilines

Federica Pisaneschi*a,b, Jimmy J. P. Sejbergb, Cecile Blainb, Wang Hei Ngb, Eric O. Aboagyea, Alan C. Spivey*b
a Comprehensive Cancer Imaging Centre, Imperial College London, Faculty of Medicine, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK
b Department of Chemistry, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK
Fax: +44(20)75945841; e-Mail: f.pisaneschi@imperial.ac.uk; e-Mail: a.c.spivey@imperial.ac.uk;
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Publication History

Received 14 December 2010
Publication Date:
10 January 2011 (online)

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Abstract

A range of 2-substituted 2,3-dihydro-1H-quinolin-4-ones have been synthesized from anilines by a two-step process involving Sonogashira coupling with a propargyl alcohol then acid-catalyzed cyclization of the resulting 2-(3′-hydroxypropynyl)anilines. The cyclization reaction appears to proceed via re­gioselective rearrangement of the propargyl alcohol to an α,β-unsaturated ketone (Rupe rearrangement) and then 6-endo-trig ring closure (Donnelly-Farrell cyclization). The isolation of the α,β-­unsaturated ketone intermediate in one example supports this pathway.

Key words

quinolinone - Sonogashira coupling - Rupe rearrangement - cyclization - alkaloids - alkynes

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General Procedure for the Sonogashira Couplings with 2-Methylbut-3-yn-2-ol (2a)
The iodo-, bromo-, or triflate-substituted aniline was dissolved in Et3N-pyridine (1:1, 0.1 M), and nitrogen was bubbled through for 10 min at r.t. 2-Methylbut-3-yn-2-ol (2a 1.5 equiv) was added, and the solution was stirred for 10 min with nitrogen bubbling through. CuI (0.05 equiv), Ph3P (0.5 equiv), and (PPh3)2PdCl2 (0.05 equiv) were then added, and the resulting suspension was heated at 90 ˚C for 1.5-3 h (see Table  [¹] ). The reaction mixture was cooled to r.t. and quenched with a sat. solution of NaCl. The mixture was then extracted twice with EtOAc, and the combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The desired products were purified by flash chromatography.
N -[2-(3-Hydroxy-3-methylbut-1-ynyl)phenyl]acetamide (3a)
Colorless oil (76% yield). ESI-HRMS: m/z calcd for C13H15NO2Na: 240.1000; found: 240.1001 (Δ = 0.4 ppm). ESI-MS: m/z (%) = 240 (95) [MNa+], 200(100). ¹H NMR (400 MHz, CDCl3): δ = 8.29 (d, J = 8.3 Hz, 1 H, 6-H), 7.81 (br s, 1 H, NH), 7.31 (dd, J = 7.7, 1.3 Hz, 1 H, 3-H), 7.26 (td, J = 8.3, 1.5 Hz, 1 H, 5-H), 6.96 (t, J = 7.4 Hz, 4-H), 2.15 (s, 3 H, CH 3CONH), 1.61 [s, 6 H, C(CH 3)2OH]. ¹³C NMR (101 MHz, CDCl3): δ = 168.4 (s, CO), 138.9 (s, Ar), 131.5 (d, Ar), 129.7 (d, Ar), 123.4 (d, Ar), 119.4 (d, Ar), 111.4 (s, Ar), 101.5 (s, 2 C, Cº), 65.7 [s, C(CH 3)2OH], 31.5 [q, 2 C, C(CH 3)2OH], 24.8 (q, CH 3CO). IR: νmax = 3360, 2924, 2853, 2400, 1662, 1523, 1447 cm-¹.

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General Procedure for the Acid-Catalyzed Cyclization
Sonogashira coupling product 3a-h was dissolved in concd HCl-H2O (1:1, v/v; 0.1 M) and heated at 120 ˚C for 1.5-8 h (see Table  [²] ). The reaction mixture was then concentrated in vacuo. Water was then added followed by K2CO3 up to pH = 11. The mixture was extracted twice with EtOAc, and the combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. Final quinolinones were purified by flash chromatography.
2,2-Dimethyl-2,3-dihydro-1 H -quinolin-4-one (4a)
Yellow oil (70% yield). ESI-HRMS: m/z calcd for C11H14NO: 176.1075; found: 176.1071 (Δ = -2.3 ppm). ESI-MS: m/z (%) = 176 (78) [MH+], 120 (100). ¹H NMR (400 MHz, CDCl3): δ = 7.83 (dd, J = 7.9, 1.4 Hz, 1 H, Ar), 7.35-7.27 (m, 1 H, Ar), 6.71 (m, 1 H, Ar), 6.63 (d, J = 8.2 Hz, 1 H, Ar), 4.18 (s, 1 H, NH), 2.61 (s, 2 H, 3-H), 1.35 [s, 6 H, NC(CH3)2]. ¹³C NMR (100 MHz, CDCl3): δ = 194.0 (s, CO), 149.8 (s, Ar), 135.4 (d, Ar), 127.2 (d, Ar), 118.1 (d, Ar), 117.5 (d, Ar), 115.8 (s, Ar), 53.6 (s, 2-C), 50.6 (t, 3-C), 27.7 (q, 2 C, CH3). IR: νmax = 3333, 2924, 2853, 1659, 1613, 1481 cm-¹.