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9. G. W. Gribble and C. F. Nutaitis, Org. Prep. Proced. Ini. 17, 317 (1985).
Ю- D. M- Ketcha, B. A. Lieurance, D. F. J. Holman and G. W. Gribble, J. Org. Chem. 54, 4350 (1989).
П. J. E. Appleton, K. N. Dack, A. D. Green and J. Steele, Tetrahedron Lett. 34, 1529 (1993).
12. D. L. Comins and E D. Stroud, Tetrahedron Lett. 21, 1869 (1986).
13. E. Reimann and E. Hargasser, Arch. Pharm. 321, 823 (1988).
15.4 OXIDATION OF INDOLES TO OXINDOLES
The conversion of indoles to oxindoles can be achieved in several ways. Reaction of indoles with a halogenating agent such as NCS, NBS or pyridin-ium bromide perbromide in hydroxylic solvents leads to oxindoles[l]. The reaction proceeds by nucleophilic addition to a 3-haloindolenium intermediate.
H H H H
Use of an excess of the halogenating agent results in halogenation at the 3-position of the oxindole[3,4]. The halogenation and hydrolysis can be carried out as two separate steps. One optimized procedure of this type used NCS as the halogenating agent and it was found that 70% phosphoric acid in
2-mcthoxyethanol was the most effective medium for hydrolysis. If the halogenation is carried out in pyridine, the intermediate is trapped as an
15.4 OXIDATION OF INDOLES TO OX1NDOLES
N-(indol-2-yl)pyridinium salt which can subsequently be hydrolysed to an oxindole.
The oxidation of 3-substituted indole to oxindoles can also be done with a mixture of DMSO and conc. hydrochloric acid[6-9]. This reaction probably involves a mechanism similar to the halogenation with a protonatcd DMSO molecule serving as the electrophile.
X = Cl or OH
A CH2C12 of 7-benzoylindole (245 g, 1 mol) was chlorinated with JV-chlorosuc-cinimide (119 g, 0.87 mol) at 15- 20 С by adding a quarter of the reagent at 0.5 h intervals. One hour later, the solution was washed with water (2.5 1 x 2). The water layer was re-extracted with CH2C12 (200 ml). After washing with an equal volume of water, the extract was combined with the original CH2C12 layer and distilled to remove the CH2C12. The residual 7-benzoyl-3-chloro-indole was dissolved in 2-methoxyethanol (1.81) and heated to 100°C. With stirring, H3PO4 (70%, 1.3 1) was added. A phosphate salt separated but stirring was continued. The mixture was maintained at reflux for 4-8 h. using TLC to monitor reaction progress. Upon completion, the mixture was treated with charcoal (20-40 g) at reflux for 15 min and then filtered hot. The filtrate was kept at 70°C while warm (65-70°C) water (2.3 1) was added with stirring. Precipitation began during the addition. The slurry was cooled slowly to 5JC and kept for 12h. Filtration then gave 7-benzoyloxindole (199 g, 84% yield).
A solution of l,3-dimethyl-5-methoxyindole (4.5 g, 0.026 mol) in DMSO (27 ml) was maintained at 5°C as conc. HC1 (23 ml, 0.77 mol) was added dropwise over 15 min. Stirring was continued for 3 h at room temperature and the reaction mixture was then poured into ice-watcr (100 ml). The mixture was neutralized with NaHC03 to pH 7 and extracted with EtOAc (100 ml x 2). The EtOAc was removed in vacuo and the residue purified by chromatography on silica using hexane-EtOAc (7:3) for elution. The yield was 4.35 g (88%).
15 SELECTIVE REDUCTION AND OXIDATION REACTIONS
1. R. L. Hinman and C. P. Bauman, J. Org. Chem. 29, 1206 (1964).
2. Y. S. Lo, D. A. Walsh, W. J. Welstead. Jr, R. P. Mays, E. K. Rose, D. H. Causey and R. L. Duncan. J. Heterocycl. Chem. 17, 1663 (1980).
3. A. Marfal and M. P. Carta, Tetrahedron Leu. 28, 4027 (1987).
4. J. Parrick, A. Yahya, A. S. Ijaz and J. Yizun, J. Chem. Soc.. Perkin Trans. I 2009 (1989).
5. T. Kobayashi and N. Inokuchi, Tetrahedron 20, 2055 (1964).
6. K. Szabo-Pusztay and L. Szabo, Synthesis 276 (1979).
7. M. Uchica, F. Tabusa, M. Komaisu, S. Morita, T. Kanbe and K. Nakagawa, Chem. Pharm. Bull. 35, 853 (1987).
8. R. Underwood, K. Prasad, O. Repic and G. E. Hardtmann, Sjwft. Commun. 22, 343 (1992),
9. S.-I. Bascop, J. Sapi. J.-Y, Laronze and J, Levy, Heierocycles 38, 725 (1994).
10. J. Hocker, K. Ley and R. Merten, Synthesis 334 (1975).
15.5 SELECTIVE OXIDATION OF SUBSTITUENTS
Because of the susceptibility of the indole ring to oxidation, most of the classical methods for oxidation of aromatic substituents are not appropriate for indole derivatives. There are, however, procedures that can effect conversion of 3-alkyl groups to 3-acyl groups and of 2-alkyl subsitutcnts to hydroxyalkyl or acyl. The preferred reagent for oxidation of 3-alkylindoles to
3-acylindoles is dichlorodicyanoquinone (DDQ). It has been used both with substituted indoles and fused ring analogues. For example, N,0-protected tryptophans can be oxidized in good yield[l].
NHCCH3 DDQ f-^\r^NHCCH3
Generally speaking though, yields are best for the fused ring derivatives. The reactions are usually carried out in 10% aq. THF and probably proceed through 3-alkylideneindolenine intermediates. Table 15.4 gives several examples. Selenium dioxide has also been used for oxidations leading to 3-acylindoles (Entry 9).