有机人名反应|Arndt–Eistert Homologation

人名反应

Arndt–Eistert Homologation

     Arndt–Eistert Homologation由Arndt和Eistert在1935年首次报道^[1]。重氮甲烷的碳被酰氯酰化，得到α-重氮酮，随后经过Wolff Rearrangement，烯酮可被亲核试剂如水、醇、氨/胺捕获。该反应可将羧酸扩展一个CH2单元。

反应机理

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反应实例

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反应操作(ref.3)：

(a) To a solution of tert-butyl (2S,3S)-3-(1-(3,5-dichlorophenyl)-2-ethoxy-2-oxoethoxy)-2-phenylpiperidine -1-carboxylate (3.0 g, 5.90 mmol) in EtOH (40 mL) and water (8 mL) was added lithium hydroxide monohydrate (1.24 g, 29.5 mmol), and the reaction was stirred at 40 °C for 2 h. The mixture then was concentrated, and to the mixture was added water (10 mL). The solution’s pH was adjusted to 4 by 2 N HCl and extracted with ethyl acetate. The collected organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford the crude acid, used in the next step without purification.

(b) The crude residue was dissolved in DCM (20 mL) and ether (10 mL) at 0 °C under N2. Then, 4-methylmorpholine (1.50 mL, 13.62 mmol) was added, followed by addition of isobutyl chloroformate (1.611 mL, 12.39 mmol) dropwise. The mixture was stirred at 0 °C for 1 h, diazomethane (5.21 g, 124 mmol) in ether was added dropwise to the reaction mixture, the reaction was stirred for 2 h. The mixture was quenched with aq. NH4Cl (25 mL) and extracted with ethyl acetate. The collected organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0−5% EtOAc in petroleum ether) to afford the tert-butyl (2S,3S)-3-(3-diazo1-(3,5-dichlorophenyl)- 2-oxopropoxy)-2-phenylpiperidine-1-carboxylate (64, 2.9 g, 5.17 mmol, 88% yield) as a colorless oil. MS: m/z = 504.2 [M + H].

(c) To a solution of tert-butyl (2S,3S)-3-(3-diazo-1-(3,5-dichlorophenyl)-2-oxopropoxy)-2phenylpiperidine -1-carboxylate (2.9 g, 5.17mmol) in MeOH (15 mL) and 1,4-dioxane (15 mL) was added a solution of silver benzoate (0.18 g, 0.78 mmol) in ethyl acetate (2.16 mL, 15.5 mmol) dropwise at 0 °C under N₂. The reaction was stirred at 19 °C for 2 h. The mixture was quenched with aq. NH4Cl (10 mL) and water (20 mL) extracted with ethyl acetate. The collected organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude which was purified by silica gel chromatography (0−7% EtOAc in petroleum ether) to give two isomers, of which the less polar isomer tert-butyl (2S,3S)-3-(1-(3,5-dichlorophenyl)-3-methoxy-3-oxopropoxy)-2-phenylpiperidine-1-carboxylate (570 mg, 1.07 mmol) was carried forward.

参考文献

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[1] F. Arndt, B. Eistert. Action of the transfer of carbon acids in their high homogenous respectively its derivative. Ber. 1935, 68, 200–208.

[2] S. Levin, R. R. Nani, S. E. Reisman. Rapid assembly of the Salvileucalin B norcaradiene core. Org. Lett. 2010, 12, 780–783.

[3] V. W. Mak,* A. M. Patel, R. Yen, J. Hanisak, Y. H. Lim, J. Bao, R. Zheng, W. M. Seganish, Y. Yu, D. R. Healy, A. Ogawa, Z. Ren, A. Soriano, G. P. Ermakov, M. Beaumont, E. Metwally, A. C. Cheng, A. Verras, T. Fischmann, M. Zebisch, H. L. Silvestre, P. A. McEwan, J. Barker, P. Rearden,T. J. Greshock. Optimization and mechanistic investigations of novel allosteric activators of PKG1α. J. Med. Chem. 2022, 65, 10318–10340.