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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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11. D. A. Walsh, H. W. Moran, D. A. Shamblee, W. J. Welstead, Jr, J. C. Nolan, L. F. Sancilio and G. Graff, J. Med. Chem. 33, 2296 (1990).
12. M, Toyota and K. Fukumoto, J. Chem. Soc.. Perkin Тгапь. I 547 (1992).
13. D. A. Walsh, H.W. Moran, D. A. Shamblee, I. M. Uwaydah, W. J. Welstead, Jr, L. F. Sancilio and W. N. Dannenbuerg, J. Med. Chem. 27, 1379 (1984).
14. Y. Fukuda, Y. Itoh, K. Nakatani and S. Tereshima, Tetrahedron 50, 2793 (1994).
15. D. A. Walsh, D. A. Shamblee, W. J. Welstead, Jr, and L. F. Sancilio, J. Med. Chem. 25, 446
(1982).
16. G. M. Karp, ./. Org. Chem. 57, 4765 (1992).
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J. Med. Chem. 35, 163 (1992).
7.4 INDOLES FROM ANILINES via o-CHLOROACETYLATION-THE SUGASAWA SYNTHESIS
Boron trichloride, usually in conjunction with an additional Lewis acid, effects ochloroacetylation of anilines. The resulting products are converted to indoles by reduction with NaBH4[l], The strength of the Lewis acid required depends upon the substitution pattern on the ring. With ER substituents no additional
76
7 CATEGORY Пас CYCLIZATIONS
Table 7.7
Indoles via o-chloroacetylanilines
Entry Substituents Acylation conditions Yield (%) Ref.
Acyl. Cycl.
1 5-Methyl BCl3/ZnCI2 62 81 Г2]
2 7-Propyl BCI3/AICI, 59 48 Г31
3 5-Methoxy-7-methyl BCl,/TiCl4 25 86 Г41
4 5-Chloro-1 -(1 -methylpipcrid-4-yl) BCI3 93 69 151
5 6,7-Dibromo-4-methoxy BCl3/TiCl4 90 90 161
6 5,6,7-Trimethoxy BCI, 85 72 [7]
catalyst may be required but in other cases TiCl4 or A1C13 is needed. Table 7.7 gives some examples of indoles prepared in this way.
CICH2
с
NaH н
Procedure
6,7-Dibromo-4-methoxyindole[6]
Chloroacetylation
A solution of 2,3-dibromo-5-methoxyaniline (32 g, 0.17 mol) in CH2C12 (300 ml) was stirred and cooled in an icc bath. Boron trichloride (1 M in CH2C12, 180 ml, 0.18 mol), chloroacetonitrile (14.3 g, 0.19 mol) and TiCl4 (1 M in CH2C12, 190ml, 0.19mol) were added. The resulting mixture was refluxed for 1.5 h. The solution was cooled to room temperature and poured carefully on to a mixture of icc and 20% aq. HCl (700 ml). The organic layer was separated and the CH2C12 removed by distillation. The residue was heated to 90°C on a water bath Гог 30 min. The solution was cooled and the solid collected by filtration. It was partitioned between ether (1.4 1) and 1 N NaOH (500 ml). The ether layer was washed with brine, dried over Na2S04 and evaporated. The residue was recrystallized from ethanol to give 2-amino-3,4-dibromo-6-methoxy-a-chloroacetophenone (55 g) in 90% yield.
7.5 THE B1SCHLER INDOLE SYNTHESIS
77
Reductive cyclization
The above product (24 g, 0.067 mol) was dissolved in 90:10 dioxane-water (300 ml) and sodium borohydride (92.5 g, 0.067 mol) was added. The mixture was refluxed for 4h. The cooled solution was poured into 0.1 N HC1 (1.11). A solid precipitated and was collected by filtration, dried and recrystallized from ether hexane to give 6,7-dibromo-4-methoxyindole (18.5 g, 90%).
References
1. T, Sugasawa, M. Adachi, K. Sasakura and A, Kitagawa, J. Org, Chem, 44, 578 (1979).
2. M, Nimtz and G. Hafelingcr, Liebigs Ann. Chem. 765 (1987),
3. R, A. Glennon, C. Chaurasia and M. Titeler. J. Med. Chem. 33, 2777 (1990),
4. R, A. Glennon, E. Schubert, J. M. Jacyno and J. A. Rosencrans, J. Med. Chem. 23, 1222 (1980).
5. M. Adachi. K, Sasakura and T, Sugasawa, Chem. Pharm. Bull. 33, 1826 (1985); K. Sasakura, M. Adachi and T. Sugasawa, Synth. Commun, 18, 265 (1988),
6. B. Jiang, J. M. Smallheer, C, Amaral-Ly and M. A, Wuonola, J, Org. Chem, 59, 6823 (1994).
7. M. J. E. Hewlins, A. H. Jackson. A.-M. Olivcira-Campos and P. V. R. Shannon, J. Chem. Soc. Perkin Trans. 1 2906 (1981),
Anilines react with a-haloacetophenones to give 2-arylindoles. In a typical procedure an /V-phenacylaniline is healed with a two-fold excess of the aniline hydrobromide to 200-250°C[l]. The mechanism of the reaction was the subject of considerable investigation in the 1940s[2], A crucial aspect of the reaction seems to be the formation of an imine of the acctophenone which can isomerize to an aldimine intermediate. This intermediate apparently undergoes cyclization more rapidly (path Ы -> b2) than its precursor (Scheme 7.3). Only with very reactive rings, e.g. 3,5-dimethoxyaniline, has the alternative cyclization (path al -> a2) to a 3-arylindole been observed and then only under modified reaction conditions[3].
7.5 THE B1SCHLER INDOLE SYNTHESIS
OH
Ar
H
H
SCHEME 7.3
78
7 CATEGORY Ilur CYCLIZATIONS
There is an experimental variation in which an iV-phenacylpyridinium salt is heated with an aniline[4]. This reaction can also be readily accommodated to the mechanism involving an imine intermediate. There are a few examples of use of other types of a-halokctones[5,6] but most of the synthetic applications have been to 2-arylindoles.
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