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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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Table 7.4 gives some examples of indoles obtained from hydrazones prepared by Japp-Klingemann coupling. Entry 6 presents a case where coupling with 2-ethoxycarbonylcyclopentanone is followed by ring cleavage to generate a precursor of an indole-3-propanoic acid. This reaction was successfully performed on a large scale (5 kg of product) using BF3 in acctic acid as the reaction medium[l].
A special application of the Japp-Klingemann/Fischer sequence is in the preparation of tryptamines from piperidone-3-carboxylate salts, a method which was originally developed by Abramovitch and Shapiro[2], When the piperidone is subjected to Japp-Klingemann coupling under mildly alkaline conditionb decarboxylation occurs and a 3-hydrazonopiperidin-2-one is isolated. Fischer cyclization then gives 1-oxotetrahydro-p-carbolines which can be hydrolysed and decarboxylated to afford the desired tryptamine.
The decarboxylation is frequently the most troublesome step in this sequence. Attempts at simple thermal decarboxylation frequently lead to recycliz-ation to the lactam. The original investigators carried out decarboxylation by acidic hydrolysis and noted that rings with ER substituents were most easily decarboxylated[2]. It appears that ring protonation is involved in the decarboxylation under hydrolytic conditions. Quinoline-copper decarboxylation has been used successfully after protecting the exocyclic nitrogen with a phthaloyl, acctyl or benzoyl group[3],
A variation on the tryptamine synthesis is to use diethyl (3-chloropropyl)-malonate as the substrate for a one-pot Japp-Klingemann/Fischer procedure. The chloropropyl group alkylates the a-nitrogen, forming the tryptamine side-chain. The precise stage at which the alkylation occurs is unclear[4].
1) pH = 6, ..
ArN2+ + С|СНгСН2СНгСН(С02СгН5)г -» Х-Ц- y-C02C2H5
2) BuOH,
Water (121) and crushed ice (12 kg) were added to a suspension of 3-amino-4-chlorobcnzoic acid (5.0 kg) in conc. HC1 (61). The mixture was stirred and kept at 0-2nC by adding more ice during addition of a solution of NaN02 (2.05 kg) in water (3 1). Stirring was continued at 0-2°C for 1 h after the addition was complete. NaOAc hydrate (5 kg) was added, followed by ethyl 2-oxocyclo-pentanecarboxylate (4.55 kg). An oil separated which eventually solidified. After 30 min the precipitate was collected as an orange solid and washed with ice-water. The solid was then added to 80% acetic acid (30 1) and the mixture was stirred at 95-100°C for 1 h. The solution was cooled and the intermediate hydrazone was collected by filtration and dried (6.6 kg, 63%). The hydrazonc (6.6 kg) was suspended in glacial acetic acid (25 1) and BF3-acetic acid complex (4.5 1) was added. The mixture was heated to 90°C with stirring. At this point an exothermic reaction began and the heat source was removed. The solution was allowed to spontaneously reflux until the exotherm subsided and then heated to reflux again for 4h. The solution was cooled and filtered. The solid product was washed with water and dried to give the product (5.1 kg, 81%).
Methyl 3-(4-fluorophenyl)-5-methylindole-2-carboxylate[8]
To a solution оГ p-toluidine (119.4 g, 1.1 mol) in conc. HC1 (580 ml) was added over 1.5 h at 0-5°C a solution of NaN02 (84.6 g, 1.2 mol) in water (500 ml). This solution was added in one portion with stirring, to a mixture of methyl
2-(4-fluorobenzyl)-3-oxobutanoate (250 g, 1.1 mol), KOH (220g, 3.9 mol) water (500 ml), ethanol (1.25 ml) and ice (2 kg). After 2 h at room temperature, the reaction solution was extracted with ether (2 x 21). The organic phases were combined, washed with water (31), dried (Na2S04) and evaporated to give the crude hydrazone (330 g) which was used without further purification. The hydrazone was dissolved in MeOH (2.251) containing conc. H2S04 (100 ml) and the solution was heated at reflux for 18 h. The solution was cooled and partially evaporated in vacuo. The product (180 g) was obtained in 58% yield.
1. R. E. Bowman, T. G. Goodbum and A. A. Reynolds, J. Chem. Si*., Perkin Trans. / 1121 (1972).
2. R. A. Abramovitch and D. Shapiro, J. Chem. Soc. 4589 (1956); R. A. Abramovitch, J. Chem. Soc. 4593 (1956).
3. S. Misztal and J. Boksa, Pol. J. Pharmacol. I’harm. 36, 345 (1984).
4. C. Szantay, L. Szabo and G. Kalaus, Synthesis 354 (1974).
5. Y. Murakami. T. Watanabe, Y. Yokoyama, J. Naomachi, H. Iwase. N. Watanabe, M. Morihata, N. Okuyama, H. Kamakura, T. Takahashi, H. Atoda, T. Tojo, K. Morita and H. Isbii, Chem. Pharm. Bull. 41, 1910 (1993).
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