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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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21. A. P. Laws and R, Taylor, J. Chem. Soc., Perkin Trans. 2 591 (1987).
22. F. G, Bordwell, X. Zhang and J.-P. Cheng. J. Ory. Chem. 56, 3216 (1991).
23. W. J. Houlihan (ed.), Chem. Heterocvcl. Cmpds 25-1, 25-11, 25-III, John Wiley & Sons, New York.
24. C. W. Bird and G. W. H. Cheeseman (eds), Compr. Helerocyci. Chem., Vol. 4. Pergamon Press, 1984,
25. Compr. Heterocvcl Chem., Second Ed., forthcoming.
26. M. A. Yurovskaya, Chem. Heterocycl. Cmpds, Enyl. Transl. 23, 919 (1987).
27. U. Pindur and R. Adam, J. Helerocyci Chem. 25, 1 (1988).
28. G. W'. Gribble, Contomp. Ory. Chem. 1. 145 (1994).
-2-
Category la Cyclizations
Category 1 a cyclizations involve formation of the N-C2 bond from a preformed intermediate which contains all the necessary atoms to construct the indole framework. One group of these cyclizations proceeds by addition-elimination at a carbonyl or imine group, as represented in retrosynthctic path a, Scheme 2.1. The starting materials are often aromatic nitro compounds, with the cyclization taking place following reductive conversion to a nudeophilic amino group. The carbonyl or imine double bond may be present in the starting material, but it can also be introduced during the synthetic process. Retrosynthetic path b involves activation of an acetylene bond to nudeophilic addition of the endo-dig type. Metal ions, especially Pd2+, are effective catalysts, with the Pd2+ being removed after cyclization by protonolysis. Rctrosynthetic path с corresponds to reaction between an electrophilic nitrogen species and an adjacent double bond. This pattern is realized synthetically by reductive conversion of o-nitrostyrenes to indoles.
2.1 INDOLES FROM (J-DIALKYLAMINO-O-NITROSTYRENES. THE LEIMGRUBER- BATCHO SYNTHESIS
The Leimgruber-Batcho synthesis is a two-step method which provides indoles that arc substituted only in the benzene ring. The method was initially disclosed in a patent[l] and a representative procedure is available in Organic Syntheses[2]. A review of the reaction is available[3]. The reaction involves
SCHEME 2.1
8
2 CATEGORY la CYCLIZATIONS
condensation of an onitrotoluene with iV.jV-dimethylformamide dimethyl-acetal. In its first version the reaction was driven to completion by distillation of methanol. An improvement which has been widely adopted is to include pyrrolidine in the reaction mixture. Under these conditions the reaction is acceleratcd and the pyrrolidine is exchanged into the enamine product[4], ms-Piperidinomethane is an alternative reagent which may be advantageous if the condensation with DMF dimethylacetal is sluggish[5]. The reaction depends on the nitro group both to acidify the methyl group and to stabilize the enamine product. The reaction is very versatile with respect to the range of carbocyclic substituents that can be used.
The second step of the synthesis involves reductive cyclization. A number of reducing agents have been used, the choice, at least in part, being dictated by the nature of the carbocyclic substituents. The reductive cyclization is usually done with hydrogen over a palladium catalyst or with Raney nickel and hydrazine. Not much is known about the exact sequence of the reduction but it is possible to obtain iV-hydroxyindoles by choice of an appropriate reagent. Zinc-NH4C1 is the preferred reductant for this purpose[6]. Use of TiCl3 as reductant gives a mixture of the indole and N-hydroxyindole[7]. These results suggest that the cyclization can take place at the hydroxylamine reduction level. Table 2.1 gives some representative examples.
Procedures
7-Methoxyindole[8]
A. Condensation step
A solution of 2-nitro-3-mcthoxytolucnc (5g, 30 mmol), DMF dimethylacetal (4.25 ml, 32 mmol) and pyrrolidine (2.5 ml, 30 mmol) in DMF (50 ml) was stirred and heated at 130 С under nitrogen for 3 h. The solvent was removed in vacuo and the residue dissolved in isopropyl alcohol (50 ml). The enamine intermediate (3.98 g, 54%) was obtained as orange crystals.
B. Reductive cyclization
A mixture of 3-methoxy-2-nitro-p-pyrrolidinostyrene (10 g, 40 mmol) and Raney nickel (25 g) in methanol-THF (40 ml of each) was heated to 60°C and,
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