Download (direct link):
It is also possible to effect 3-alkylation via reactions of 3-lithioindoles.
3-Lithioindoles are not as easily available nor quite as easy to use as the
2-isomers. They are ordinarily prepared by halogen-metal exchange between a haloindole and an alkyllithium reagent. The stability of the 3-lithioindoles depends on the nitrogen substituent. With a 1-phenylsulfonyl substituent rearrangement to the more stable 2-lithioindole occurs at temperatures of — 40°C and above. This problem can be avoided by use of a ferf-butyl-dimethylsilyl (TBDMS) protecting group. 3-Lithio-l-TBDMSindole can be prepared from 3-bromo-l-TBDMSindole and is stable up to room tempera-ture. The steric bulk of the protecting group evidently retards rearrangement of lithium to C2. 3-Lithioindoles prepared by halogen metal exchange undergo typical alkylation reactions[25,26].
3-Alkylation by conjugate addition
Entry Indole reactant Electrophile Yield (%) Ref.
1 Indole But-3-en-2-onc, 4:1 AcOH, Ac20, 25°C -> 90 C 75 
2 Indole But-3-en-2-one, BF,, EtOH, -2(ГС 86 
3 Indole But-3-en-2-one, CH2C12, montmorillonite clay, 40'C 75 
4 Indole Nitroethene, benzene, 0 C then 25"C for 20 h 80 
11 INTRODUCTION OF SUBSTITUENTS ЛТ C3
2) BF3 OEt2
There are also palladium-catalysed procedures for allylation. Ethyl 3-bromo-l-(4-methylphenylsulfonyl)indole-2-carboxylate is allylated at C3 upon reaction with allyl acetate and hexabutylditin. The reaction presumably involves a 71-allyl-Pd intermediate formed from the allyl acetate, oxidative addition, transmetallation and cross coupling.
A 20% excess of ethylmagnesium bromide was prepared from magnesium (6.5 g) in ether (80 ml) by adding ethyl bromide (30 g) in ether (30 ml). Indole (25.8 g) in benzene (50 ml) was then added slowly with stirring and stirring was continued for 20 min after addition was complete. A solution of allyl bromide (29.2 g) in benzene (20 ml) was then added slowly. The mixture was stirred overnight and then diluted with ether and the product isolated and purified by distillation (22.7 g, 70% yield).
A solution of benzyl indole-5-carboxylate (1.0 g, 3.98 mmol) and methyl 4-(bro-momethyl)-3-methoxybenzoate (2.06 g, 7.97 mmol) in dry DMF (10 ml) was heated at 80°C for 24 h. The reaction solution was cooled, poured into water (100 ml) and the product extracted with EtOAc (3 x 75 ml). The extract was washed with water and brine and dried over MgS04. The product was obtained by evaporation of the solvent and purified by chromatography on silica gel using 1:4 EtOAc/'hexane for elution. The yield was 1.11 g (32%) and some of the indole (30%) was recovered unreacted.
11.2 VINYLATION, ARYLATION AND ALKYNYLATION
1. B. Cardillo, G. Casnati, A. Pochini and A. Ricca, Tetrahedron 23, 3771 (1967).
2. H. Heaney and S. V. Ley, J. Chem. Soc. Perkin Trans. 1 499 (1973).
3. S. Nunomoto. Y. Kawakami, Y. Yamashita. H. Takeuchi and S. Eguchi, J. Chem. Soc., Perkin Trans. 7 111 (1990).
4. J. B. Brown, H. B. Henbest and E. R. N. Jones. J. Chem. Soc, 3172 (1952).
5. C. W. Holzapfel, K. Bischofberger and J, Olivier, Synth. Commun. 24, 3197 (1994).
6. M. Sainsbury, D. Weerasinghe and D. Dolman, J. Chem. Soc., Perkin Trans. J 587 (1982).
1. G. Casnati, M. Francioni, A. Guareschi and A. Pochini, Tetrahedron Lett. 2485 (1969).
8. K. J. Henry, Jr and P. A. Grieco, J. Chem. Soc., Chem. Commun. 510 (1993).
9. R. T. Jacobs, F. J. Brown, L. A. Cronk, D. Aharony, С. K. Buckner, E. J. Kusncr, К. M. Kirkland and K. L. Neilson, J. Med. Chem. 36, 394 (1993).
10. R. K. Bramley, J. Caldwell and R. Grigg, J. Chem. Soc.. Perkin Trans. J 1913 (1973).
1L C. W. G. Fishwick, A. D. Jones and М. B. Mitchell, Heterocycles 32, 685 (1991).
12. J.-G Rodriquez and A. San Andres, J. Heterocycl. Chem. 28, 1293 (1991).
13. H. Kuhn and O. Stein, Chem. Ber. 70, 567 (1937).
14. J. E. Audia and N. Colocci, Tetrahedron Lett. 32, 3779 (1991).
15. H. Akita, T. Kaw'aguchi, Y, Enoki and T. Oishi, Chem. Pharm. Bull. 38, 323 (1990).
16. K. Sato and A. P. Kozikowski, Tetrahedron Lett. 30, 4073 (1989).
17. I. Shima, M Shimazaki, K. Imai, K. Henimi and M. Hashimoto, Chem. Pharm. Bull. 38, 564
18. J. L. Archibald, T. Baum and S. J. Childrens, J. Med. Chem. 13, 138 (1970).
19. A. P. Gray and W. L. Archer, J. Am. Chem. Soc. 79, 3554 (1957),
20. J. Szmuszkovicz, J Am. Chem, Soc. 79. 2819 (1957),
21. G. Dujardin and J.-M. Poirier. Bull. Soc. Chim. Fr. 131, 900 (1994).
22. Z. Iqbal. A. ll Jackson and K. R, Nagaraja Rao. Tetrahedron Lett. 29. 2577 (1988).
23. D. Ranganathan, С. B. Rao, S Ranganathan, A, K. Mehrotra and R. Iyengar, J. Org. Chem. 45, 1185 (1980).
24. M. G. Saulnier and G. W. Gribble, J. Org. Chem. 47, 757 (1982).