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Synlett 2007(5): 0775-0779  
DOI: 10.1055/s-2007-967982
LETTER
© Georg Thieme Verlag Stuttgart · New York

Rhodium Carbenoid Induced Cycloadditions of Diazo Ketoimides Across Indolyl π-Bonds

Xuechuan Hong, José M. Mejía-Oneto, Stefan France, Albert Padwa*
Department of Chemistry, Emory University, Atlanta, GA 30322, USA
Fax: +1(404)7276629; e-Mail: chemap@emory.edu;
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Publication History

Received 15 September 2006
Publication Date:
08 March 2007 (online)

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Abstract

A series of diazo ketoimides prepared from (1H-indol-3-yl)acetyl chloride and alkyl 2-diazo-3-(3-substituted-2-oxopiperidin-3-yl)-3-oxopropanoates were treated with rhodium(II) acetate. Attack of the imido carbonyl oxygen at the resultant rhodium carbenoid center produced a transient push-pull carbonyl ylide dipole which underwent an intramolecular dipolar cycloaddition across the indole π-bond. In most cases, the resulting cycloadduct is the consequence of endo-cycloaddition with respect to the dipole and this is fully in accord with the lowest energy transition state. Interestingly, when a tert-butyl acetate substituent is located at the ring juncture of the starting diazo ketoimide, the exo-cycloadduct was the exclusive product obtained. In this case, the bulky tert-butyl ester functionality blocks the endo-approach thereby resulting in the ­cycloaddition taking place from the less congested exo-face.

Key words

rhodium(II) - diazo - catalyst - carbonyl ylide - dipolar cycloaddition - indole - kopsifoline - alkaloid

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Frontiers in Organic Synthesis; Wender, P. A., Ed.; Chem. Rev. 1996, 96, 1-600.

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In a typical general procedure, 1.1 equiv of the appropriate 3-indoleacetic acid was dissolved in CH2Cl2 and 4.0 equiv of oxalyl chloride was added dropwise. The solution was stirred overnight and then concentrated under reduced pressure. The resulting solid was taken up in THF, which was immediately added to a vigorously stirred mixture containing 1.0 equiv of the diazo lactam (i.e. 19 or 20) and 4 Å MS in THF. After stirring for 12 h, the mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The crude material was purified by flash silica gel column chromatography to give the desired coupled product. Using this procedure, 3-{3-(2-benzyloxyethyl)-1-[2-(1-methyl-1H-indol-3-yl)acetyl]-2-oxopiperidin-3-yl}-2-diazo-3-oxopropionic acid methyl ester (16d) was obtained as a colorless oil in 82% yield. IR (neat): 2143, 1718, 1685, 1332, 1146 cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.65-1.75 (m, 1 H), 1.85-2.02 (m, 2 H), 2.19-2.30 (m, 3 H), 3.46-3.53 (m, 1 H), 3.61-3.80 (m, 2 H), 3.70 (s, 3 H), 3.76 (s, 3 H), 4.15-4.21 (m, 1 H), 4.24 (s, 2 H), 4.37 (d, 1 H, J = 15.8 Hz), 4.41 (d, 1 H, J = 15.8 Hz), 6.88 (s, 1 H), 7.07-7.11 (m, 1 H), 7.17-7.32 (m, 7 H), 7.54 (d, 1 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ = 19.5, 30.2, 32.7, 34.7, 35.5, 44.5, 52.5, 59.3, 67.2, 73.0, 107.9, 109.3, 119.1, 119.2, 121.6, 127.6, 127.7, 128.2, 128.3, 128.5, 136.9, 138.4, 161.6, 173.6, 176.4, 190.8.
To a solution of 0.2 g of the diazoimide 16d in 10 mL of benzene under N2 was added 2 mg rhodium(II) acetate, and the mixture was heated at reflux for 1 h. The mixture was allowed to cool to r.t. and was filtered through a pad of Celite®. The solvent was removed under reduced pressure and the residue was subjected to flash silica gel chromatog-raphy to give 0.16 g (96%) of the dipolar-cycloaddition product 21d.

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The X-ray crystal structure analysis will be reported elsewhere.