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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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with stirring, hydrazine hydrate (4 ml in 30 ml of THF) was added over 60 min. The reaction mixture was then cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo and the residue purified by chromatography through silica gel using 10% ether in hexane for elution. The fractions containing product were combined and evaporated to give the product as a dear oil (2.94g, 50%).
A. Condensation step
(m-Piperidinomethane (9.20 g, 34.7 mmol) and 2-benzyloxy-6-nitrotoluene (5.62 g, 23.1 mmol) were fused together under aspirator vacuum at 110°C and stirred for 6h. The reaction mixture was coolcd and abs. methanol (100 ml) was added. The bright-red product (7.31 g, 93%) crystallized and was collected by filtration.
B. Reductive cyclization
2-Benzyloxy-6-nitro-(3-piperidinostyrene (5.00 g, 14.8 mmol) was added to a suspension of nickel boride in absolute ethanol which had been prepared from nickel acetate (15 mmol). The reaction mixture was heated to reflux. Hydrazine hydrate (1.5 g, 30 mmol) in abs. ethanol (25 ml) was added over a period of 15 min, during which vigorous gas evolution occurred. After cooling, the reaction mixture was filtered through Celite. [CAUTION: Raney nickel can ignite during filtration.] The filtrate was concentrated and the product purified by flash chromatography through silica gel using 1:1 toluene-cyclohexane for elution. The product (2.98 g, 90%) was obtained as a white solid.
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A two-step synthesis of indoles from o-nitrobenzaldehydes proceeds by condensation with nitromcthanc followed by reductive cyclization. Like the Leim-gruber Batcho method, the principal application of the reaction is to indoles with only carbocyclic substituents. The formation of the o,(3-dinitrostyrenes is usually done under classical Henry condensation conditions but KF/18-crown-6 in propanol was found to be an advantageous reaction medium for acetoxy-substituted compounds[1], The o,p-dinitrostyrenes can also be obtained by nitration of p-nitrostyrenes[2].
Several different reducing agents have been used in the reductive cyclization. Iron powder is the traditional choice but the work-up of such reactions is sometimes complicated by iron-containing precipitates. A procedure involving iron powder with a slurry with silica has been recommended[2]. Transfer hydrogenation using Pd/'C and ammonium formate is also a convenient method for reduction[3]. There is little definitive evidence of the mechanism of the reductive cyclization of o,fi-dinitrostyrenes. Certain reduction conditions lead to other products. For example, NaBH4 leads to the reduction of only the styrene double bond[4] and formation of o-nitrophenylacetoximes has been observed occasionally[5]. Table 2.2 gives some typical procedures.
5-Chloro-2-nitrobenzaldchydc (122.9 g) and nitromethane (40.4 g) were dissolved in methanol (132 ml) and cooled to 10-15°C. Л solution of NaOH (27.8 g) in water (67 ml) was added at such a rate that the temperature was maintained below 15°C by ice-bath cooling. The solution was kept in the ice bath for 2h and the resulting mass was slurried with 700 ml of ice and water. The resulting
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