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Synlett 2008(11): 1734-1736  
DOI: 10.1055/s-2008-1077875
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 3-Alkyl-1H-quinolin-2-ones via Palladium-Catalyzed Intramolecular Cyclization of Benzyl Halides and α,β-Unsaturated Amides

Zhangqin Liua,b, Changqing Shia,b, Yuanwei Chen*a
a Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
Fax: +86(28)85232228; e-Mail: chenyw@cioc.ac.cn;
b Graduate School, Chinese Academy of Sciences, Beijing 100039, P. R. of China
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Publication History

Received 1 March 2008
Publication Date:
11 June 2008 (online)

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Abstract

An efficient synthesis of 3-alkyl-1H-quinolin-2-ones was achieved in high yield (up to 91%) via Pd2(dba)3-catalyzed intramolecular cyclization of benzyl halides and electron-deficient olefins, followed by treatment with DBU.

Key words

palladium - cyclization - benzyl halides - electron-deficient olefins - quinolinone

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Typical Procedure for the Synthesis of N -Acetyl- N -[2-(bromomethyl)phenyl]acrylamide (1a) Acryloyl chloride (0.99 g, 11 mmol) was dropped slowly to the mixture of 2-[(trimethylsilyloxy)methyl]benzamine (1.95 g, 10 mmol) and 1 equiv Et3N in CH2Cl2 at 0 °C. After the reaction was complete, the solvent was removed, and the white solid was dissolved in MeOH, and then K2CO3 (2 equiv) was added. The reaction mixture was stirred for additional 2 h at r.t. and concentrated. The residue was dissolved in EtOAc and washed with H2O. The organic extracts were dried (Na2SO4) and concentrated in vacuo. Flash chromatography (EtOAc-light PE = 20:80) of the residue gave N-[2-(hydroxymethyl)phenyl]acrylamide (1.45 g, 8.19 mmol) in 81.9% yield as a white solid. Then, PBr3

(1 equiv) was dropped slowly to the solution of N-[2-(hy-
droxymethyl)phenyl]acrylamide in CH2Cl2 at 0 °C and stirred for 30 min. The reaction mixture was quenched with H2O, and the aqueous layer was extracted with additional CH2Cl2, and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 by using 10% EtOAc-light PE as eluent to give N-[2-(bromometh-
yl)phenyl]acrylamide in 73% yield as a white solid. Then acetyl chloride (3 equiv) was added to N-[2-(bromo-
methyl)phenyl]acrylamide (5 mmol, 1.195 g) and CaH2 (3 equiv), and stirred in dry THF for 24 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on SiO2 by using 8% EtOAc-light PE as eluent to give acrylamide N-acetyl-N-[2-(bromomethyl)phenyl]acrylamide in 90% yield as a white solid.

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Acetyl protection of acrylamide 1a is necessary to increase its activity.

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Typical Procedure for the Cyclization of N -Acetyl- N -[2-(bromomethyl)phenyl]acrylamide
Under the nitrogen atmosphere, the mixture of acrylamide derivative N-acetyl-N-[2-(bromomethyl)phenyl]acrylamide (1 mmol, 0.281 mg), Pd2(dba)3 (2.5 mol%), dppf (5 mol%), and Et3N (3.0 equiv) was stirred in 5 mL refluxing MeCN for 5 h. Then, DBU (1 equiv) was added and the reaction mixture was refluxed for an additional 3 h. Solvent was removed and the residue was purified by flash chromatography on SiO2 by using 20% EtOAc-light PE as eluent to give 2a in 91% yield as a white solid.

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Analytical Data of 3-(3-Nitrobenzyl)quinolin-2(1 H )-one (2c) R f = 0.25 (25% EtOAc-light PE); mp 206-209 °C. 1H NMR (300 MHz, CDCl3): δ = 12.27 (s, 1 H, NH), 8.29 (s, 1 H, ArH), 8.10-8.07 (d, 1 H, ArH), 7.73-7.70 (d, 1 H, ArH), 7.63 (s, 1 H, ArH), 7.52-7.44 (m, 3 H, ArH), 7.32-7.19 (m, 2 H, ArH), 4.10 (s, 2 H, CH2). 13C NMR (300 MHz, CDCl3): δ = 163.8, 148.3, 141.5, 138.2, 137.8, 135.4, 131.6, 130.2, 129.3, 127.4, 124.2, 122.8, 121.6, 119.9, 115.7, 36.4. ESI-MS: m/z calcd for C16H12N2O3: 280.0848; found: 281.0921 [M + H].