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Synlett 2008(1): 77-82  
DOI: 10.1055/s-2007-992411
LETTER
© Georg Thieme Verlag Stuttgart · New York

Microwave-Enhanced Fischer Reaction: An Efficient One-Pot Synthesis of γ-Carbolines

Jing Chen, Weiliang Chen, Yongzhou Hu*
ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Zijingang Campus, Hangzhou, 310058, P. R. of China
Fax: +86(571)88208460; e-Mail: huyz@zju.edu.cn;
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Publication History

Received 4 October 2007
Publication Date:
11 December 2007 (online)

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Abstract

γ-Carbolines were obtained in a simple one-pot Fischer reaction starting from N-acetyl-3-bromo-4-piperidone hydrobromide and substituted arylhydrazine hydrochlorides in acidic media under microwave irradiation or by a thermal process. The optimization procedures are reported in detail, and the results from microwave processes are compared with conventional ones.

Key words

γ-carbolines - N-acetyl-3-bromo-4-piperidone hydrobromide - arylhydrazine hydrochloride - Fischer reaction - microwave irradiation

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General Procedure for the Conventional Synthesis of γ-Carbolines 5A mixture of N-acetyl-3-bromo-4-piperidone hydrobromide 6 (1 mmol; prepared according to ref.18) and substituted arylhydrazine hydrochloride 7 (1.5 mmol) in 5 mL glacial AcOH or BF3·OEt was stirred and refluxed for 12 h. After cooling down, the mixture was neutralized with aq Na2CO3 and extracted with EtOAc (3 × 20 mL). The extract was dried over anhyd Na2SO4 and concentrated in vacuo to give crude product, which was further purified by silica column chromatography (using different ratio of PE-EtOAc-EtOH as eluent according to different products).General Procedure for the Microwave-Assisted Synthesis of γ-Carbolines 5A mixture of N-acetyl-3-bromo-4-piperidone hydrobromide (6, 1 mmol) and substituted arylhydrazine hydrochloride 7 (1.5 mmol) was placed in a microwave test tube (10 mL) containing a magnetic stirring bar and 5 mL glacial AcOH or BF3·OEt. The test tube was placed in the microwave cavity (InitiatorTM 2.0, Biotage, 400 W, 2450 MHz) and subjected to microwave irradiation at 230 °C for 5 min. After completion of the reaction, the tube was removed and cooled to r.t. The following workup and purification of the crude product was quite the same as above.

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All compounds gave satisfactory analytical and spectral data. Data for selected compounds are as follows:6-Bromo-γ-carboline (5f): white powder; mp 282-283 °C (PE-EtOAc-EtOH). 1H NMR (400 MHz, DMSO-d 6): δ = 11.87 (s, NH), 9.38 (s, 1 H), 8.50 (d, J = 1.6 Hz, 1 H), 8.45 (d, J = 5.6 Hz, 1 H), 7.61 (dd, J = 8.8, 1.6 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.49 (d, J = 5.6 Hz, 1 H). 13C NMR (100 MHz, DMSO-d 6): δ = 144.8, 144.0, 143.2, 138.4, 129.1, 123.3, 122.7, 118.6, 113.5, 112.2, 106.7. ESI-MS: m/z = 247 [M + 1]+. Anal. Calcd for C11H7BrN2: C, 53.47; H, 2.86; N, 11.34. Found: C, 53.57; H, 2.67; N, 11.23.8-Chloro-γ-carboline (5h): white powder; mp 219-220 °C (PE-EtOAc-EtOH). 1H NMR (400 MHz, DMSO-d 6): δ = 12.15 (br s, NH), 9.38 (s, 1 H), 8.48 (d, J = 5.6 Hz, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.53 (d, J = 5.6 Hz, 1 H), 7.31 (t, J = 8.0 Hz, 1 H). 13C NMR (100 MHz, DMSO-d 6): δ = 145.0, 144.0, 143.3, 136.6, 126.0, 122.8, 121.2, 119.6, 119.5, 115.8, 106.9. ESI-MS: m/z = 203 [M + 1]+. Anal. Calcd for C11H7ClN2: C, 65.20; H, 3.48; N, 13.82. Found: C, 65.25; H, 3.25; N, 13.89.