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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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9. В. C. Pearce, Synth. Commun. 22, 1627 (1992)
10. Y. Yang and A. R. Martin, Heterocycles 34, 1395 (1992).
11. S. K. Davidsen, J. B. Summers. D H. Albert, J. H. Holms, H. R. Heyman, T. J. Magoc, R, G. Conway, D A Rhein and G. W. Carter, J. Med, Chem. 37, 4423 (J994).
Selective Reduction and Oxidation Reactions
While catalytic reduction of the indole ring is feasible, it is slow because of the aromatic character of the C2-C3 double bond. The relative basicity of the indole ring, however, opens an acid-catalysed pathway through ЗЯ-indolenium intermediates.
A traditional method for such reductions involves the use of a reducing metal such as zinc or tin in acidic solution. Examples are the procedures for preparing l,2,3,4-tetrahydrocarbazole[l] or ethyl 2,3-dihydroindole-2-carbox-ylate[2] (Entry 3, Table 15.1). Reduction can also be carried out with acid-stable hydride donors such as acetoxyborane[4] or NaBH3CN in TFA[5] or HOAc[6]. Borane is an effective reductant of the indole ring when it can complex with a dialkylamino substituent in such a way that it can be delivered intramolecularly[7]. Both NaBH4-HOAc and NaBH3CN-HOAc can lead to N-ethylation as well as reduction[8]. This reaction can be prevented by the use of NaBH3CN with temperature control. At 20°C only reduction occurs, but if the temperature is raised to 50°C N-ethylation occurs[9]. Silanes can also be used as hydride donors under acidic conditions[10]. Even indoles with EW substituents, such as ethyl indole-2-carboxylate, can be reduced[ll,12].
Ethyl 2,3-dihydroindole-2-carboxylate[2]
Ethyl indole-2-carboxylate (45.2 g, 0.238 mmol) was dissolved in abs. EtOH (450 ml) in a 11 polyethylene container and cooled in a dry icc-ethanol bath. The solution was saturated with dry HCl gas until the volume increased to 875 ml, Granular tin metal (84.2 g, 0.710 mmol) was added to the slurry and
Table 15.1
Reduction of indoles to 2,3-dihydroindoles
Entry Indole substituents Reduction conditions Yield (%) Ref.
1 None NaBH,CN, HOAc, 50°C 60a [9]
2 None Zn, II,P04 64 [10]
3 2-(Ethoxycarbonyl) Sn. HC1, EtOH 62 [2]
4 1,2-Dimethyl NaBH,CN. HOAc 92 [5]
5 2-(Ethoxycarbonyl)-l-methyl EtvSiH. TFA 67 [12]
6 5,6-Dimethoxy NaBH,CN, HOAc 86 [14]
7 3-(2-Benzyloxycarbonylethyl)- 5-methoxy NaBHjCN, HOAc 87 [6]
8 5,6-Dimetboxy-2-methyl-3-[2-(4- phenylpiperazino)ethyl] Et3SiH, TFA 80 [lib]
9 2-(Methoxycarbonyl)pyrrolo[3,2-e] NaBHjCN. HOAc 79 [15]
10 5- H ydroxy-6-1 -(Methoxycarbon yl )-(phenylsulfonyl)-8-methyl-pyrrolo[3,2-e] EtjSiH. TFA 80 [13]
11 5-Benzyloxy-2-(benzyloxycarbonyl)- 4-methoxypyrrolo[3,2-e] NaBH3CN. HOAc >63 [16]
3The product is l-ethyl-2.3-dihydroindole.
the container was sealed in a precooled 1.41 autoclave which had all surfaces coatcd with siliconc oil. The sealed autoclavc was kept at room temperature for 36 h and then vented. The reaction mixture was filtered through sintered glass and chilled to — 15 ’C overnight. A yellow crystalline tin complex (73.6 g) was obtained. This complex was dissolved in abs. EtOH (750 ml). cooled and treated with anhydrous ammonia until the pH reached 8. The EtOH was evaporated and the residue slurried with ether and filtered. The solid was washed with several portions of ether. The ether filtrate and washes were combined and extracted with 1:1 water-saturated brine (300 ml) to remove basic tin salts. The ether layer was dried (MgS04) and evaporated to leave an oil which spontaneously crystallized. Recrystallization from hexane gave pure product (28.5 g, 62%).
Benzyl 2,3-dihydro-1 -benzoyl-5-methoxyindole-3-propanoate[6]
A solution of benzyl 5-methoxyindole-3-propanoate (26.0 g, 0.084 mol) in HOAc (500 ml) was cooled as NaBH3CN (26 g, 0.41 mol) was added. The resulting mixture was stirred at room temperature for 3.5 h and then poured into cold water (21). The mixture was extracted with several portions of CH2C12 and the extracts were washed with aq. NaHC03 and dried over Na2S04. Removal of the solvent gave the crude product as a viscous oil. This
material was dissolved in CHC13 and cooled in ice. Pyridine (8ml, O.lOmol) and then benzoyl chloride (11.5ml, O.lOmol) were added. The mixture was stirred for 1 h at room temperature. The reaction mixture was washed with water, aq. NaHC03 and brine and then dried (Na2S04). The solvent was removed and the residue was dissolved in EtOAc and eluted through a short Florisil column using additional EtOAc. Evaporation of the eluate and crystallization of the residue from toluene/hexane gave the product (30.2 g, 87%).
Ethyl 3-acetyl-5-hydroxy-8-methyl-6-(phenylsulfonyl)- 1,2,3,6-tetrahydrobenzo[ 1,2-b:4,3-kf Jdipyrrole-1 -carboxylate
To a stirred ice-cold solution of ethyl 3,6-dihydro-5-hydroxy-8-methyl-6-(phenylsulfonvl)benzo[l ,2-b:4,3-b']dipyrrole-1 -carboxylate (368 mg, 0.85 mmol) in TFA (3 ml) was added Et3SiH (1.5 ml). After 15 min the solution was allowed to come to room temperature and stirred for an additional 2 h. The solution was evaporated in vacuo and the residue dissolved in CH2C12 (10 ml), washed, with aq. NaHC03 and dried over MgS04. The solution was mixed with Ac20 (1ml) and CH2C12 (I ml) and kept at room temperature for 2 h. The reaction mixture was evaporated and the residue purified by chromatography on silica gel using CH2Cl2-EtOAc (3:1) for elution. The product (271 mg) was obtained in 71% yield.
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