Syntheses Of Indoles And Study On Related Questions

Indole is an important fine chemical widely used for the syntheses of pharmaceuticals, agricultural chemicals, perfumes, dyes, and additives to foods and feed stocks. 3-Methyl indole and 5-methoxy indole are important intermediates to a number of useful indole derivatives. Therefore, facile and economical syntheses of these articles are intensively pursued by research workers in the field.During initiation of this research, the first thing came to our mind was to take advantage of the superfluous supply of o-nitro ethylbenzene as starting material which was a byproduct from production of chloramphenicol by a unique process developed years ago in China. There was a presumption in our mind at the time that functionalization of the ethyl side chain on benzene ring might help to moderate the indole producing temperature, and consequently increase the selectivity of the reaction. Then upon this assumption, we formulated scheme 1 to approach the solution. Scheme 1 was to start from o-nitro ethylbenzene. Conventional sequence of oxidation and reduction was expected to give high yield of 2-(1-hydroxyethyl)-aniline which was to be submitted to indole synthesis. However, experimental results from every step failed our expectation and the last step to indole gave only a low yield of 18.8%. This forced us to give up further development work on this scheme.Scheme 2 took references from the published work of Watanabe and that of Ryuichi. Using o-nitro toluene as starting material, hydroxymethylation with formaldehyde under alkaline conditions gave o-nitro phenyl ethanol. In this study we chose to develop a Raney Ni catalyst used both for reduction of the nitro group as well as for the indole production in the last step. The final result for the three consecutive steps came as 77.7% based on o-nitro toluene. Systematic studies gave the following results:1 We conceived that the hydroxymethylation reaction to o-nitro phenyl ethanol is a reversible reaction and the reaction conditions were optimized. We found that 20% aqueous NaOH solution as alkaline catalyst, at a temperature of 50℃, and formaldehyde to o-nitro toluene molar ratio of 0.4~0.5 gave best result.2 Studies on the gradual reduction of alkalinity during hydroxymethylation reaction revealed that formaldehyde was undergoing Cannizzaro reaction to form formicacid which neutralized the catalyst NaOH to form sodium formate.3 Studies on catalytic hydrogenation with Raney Ni showed the reaction could best be carried out under conditions of 110℃with or without addition of solvent. The activity of Raney Ni was stable.4 It occurred to us that, in using Raney Ni as catalyst for indole formation, the reaction might have proceeded first by dehydrogenation of the side chain ethanol group to form an aldehyde, and then by joining with the amino group to form the ring. Addition of noble metal elements (with the exception of Ruthenium) could enhance the Raney Ni activity while Palladium showed the highest effect. Further addition of triphenyl phosphine enhanced the effect even more. While addition of triphenyl phosphine to Raney Ni-Rh system showed optimal result. However, it had no effect at all to simple Raney Ni.5 It was observed that, when this Raney Ni catalytic system was exposed to air under high temperature, dimmerization of indole might occur. And the polymer isolated was identified as 2,3'-diindolyl.Now, come back to o-nitro ethylbenzene. Running parallelly the reaction sequence of hydroxymethylation, hydrogenation and Raney Ni catalytic indole ring formation, we obtained the desired product 3-methyl indole smoothly at an overall yield of about 70%.Finally, for the synthesis of 5-methoxy indole, we formulated two schemes. Scheme 1 started from o-nitro ethylbenzene. It was actually a model study of Bamberger reaction to test the method for an extended Bamberger reaction to give 5-methoxy substituent. Scheme 2 started from o-nitro toluene again. After the hydroxymethylation step, the compound was reduced by zinc dust in the presence of ammonium chloride to a hydroxylamine. And then an extended Bamberger rearrangement formed the"5-methoxy". Finally indole ring formation was effected by the RuCl2(PPh3)3 catalyst, a catalyst adaptable to many indole syntheses with vulnerable structures. From 2-(β-hydroxyethyl)-nitrobenzene (o-nitro phenyl ethanol), the 3-step reactions (reduction, Bamberger rearrangement, and indole ring formation) gave yields of 62%, 27.6%, and 89.9%, approximately 15% overall.