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Indoles - Sundberg R.J.

Sundberg R.J. Indoles - Academic press, 1996. - 95 p.
ISBN 0-12-676945-1
Download (direct link): indoles1996.djvu
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I. M. Uwaydah, W. J. Welstead, Jr, L. F. Sancilio and W. N. Dannenburg, J. Med. Chem. 27,
1379 (1981).
14.2 RING METALLATION
Carbocyclic substitution can also be achieved by first introducing a reactive organometallic substituent. Preparation of organ olithium reagents can be done by one of the conventional methods, especially halogen-metal exchange or directed lithiation. Table 14.2 gives examples.
A study of conditions for halogcn-metal exchange of the C-bromoindoles found that the best results were obtained if the indole was first converted to its potassium salt by reaction with KH in ether at 0°C. Halogen-metal exchange was then done with t-butyllithium at — 78°C[1]. Attempts to use excess r-butyllithium on the neutral indole were not as reproducible or effective and this was attributed to complications resulting from both incomplete jV-depro-tonation and heterogeneity. Using optimal lithiation conditions, electrophiles such as DMF, jV-methyl-N-methoxyearboxamides and dimethyl disulfide gave good yields of С-substituted indoles[l,2]. Directed lithiation should also be an appropriate procedure for preparation of С-substituted indoles. Most examples in the literature have been the result of specific synthetic objectives rather than comprehensive studies of directed lithiation. Nevertheless, they indicate the potential of the methodology. One of the issues which must be considered is competition with 2-lithiation. A study of 5-methoxy-l-methylindole observed competition between C2, C4 and C6 lithiation[3]. Such competition can be influenced by proper choice of substituents. Bulky N-silyl substituents can retard C2 lithiation. For example, while l-methyl-3-(dimethylaminomethyl)-indole is lithiated at C2, use of an .V-ftri-isopropylsilyl) protecting group leads to C4 lithiation[4], 5-(Dimethylcarbamoyloxy)-l-(ferf-butyldimethylsilyl)-indole is cleanly lithiated at C4[5], 1-rerr-Butoxycarbonylindoline is lithiated at C7 and this permits introduction of various electrophiles at the 7-posi-tion[6]. These lithiated intermediates permit the introduction of various functional groups by reaction with electrophiles or they can be converted to other organometallic reagents for Pd-catalysed coupling (see Section 14.3 for examples).
Directed thallation has been useful for synthesis of some 4- and 7-substituted indoles. Electrophilic thallation directed by 3-substituents is a potential route to 4-substituted indoles. 3-Formyl[7], 3-acetyl[8] and 3-ethoxycarbonyl[7] groups can all promote 4-thallation. 1-Acetylindoline is the preferred starting
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14.3 PALLADIUM-CATALYSED SUBSTITUTION
141
material for 7-thallation[7]. The thallium can then be replaced by various functional groups including halogen[8-10], mtro[7] and azido[7], or subjected to Pd-catalyscd coupling[l 1].
Procedure
lndole-7-carboxaldehyde[ 1 ]
Potassium hydride (1 eq.) was washed with hexanes and suspended in anhydrous ether at 0°C. 7-Bromoindole was added as a solution in ether. After 15 min, the solution was cooled to — 78°C and f-butyllithium (2 eq.) which had been precooled to — 78°C was added by cannula. A white precipitate formed. After 10 min DMF (2 eq.) was added as a solution in ether. The reaction mixture was allowed to warm slowly to room temperature and when reaction was complete (TLC) the suspension was poured into cold 1 M H3P04. The product was extracted with EtOAc and the extract washed with sat, NaHC03 and dried (MgS04). The product was obtained by evaporation of the solvent and purified by chromatography on silica gel (61% yield).
References
1. M. P. Moyer, i. F. Shiurba and 11. Rapoport, J. Org. Chem. 51, 5106 (1986).
2. Y, Yang. A. R. Martin, D. L. Nelson and J Regan, Heterocycles 34, 1169 (1992).
3. R. J. Sundbcrg and R. L. Parton, J. Org. Chem. 41, 163 (1976).
4. M. Iwao, Heterocycles 36, 29 (1993).
5. E. J. Griffen, D. G. Roe and V. Snicckus, J Org. Chem. 60, 1484 (1995).
6. M. Iwao and T. Kuraishi, Heierocycle.s 34, 1031 U992).
7. M. Somei, F. Yamada, H. Hamada and T. Kawasaki, Heterocycles 29, 643 (1989).
8. R. A. Hollins. L, A. Colnago. V. M. Salim and М. C. Seidl, J Heterocycl. Chem. 16, 993 (1979).
9. T. Ohta, Y. Yamato, H. Tahira and M. Somei, HeterocycleLs 26. 2817 (1987).
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