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3-[(2-Dimethylamino)ethyl]-5-(1-pyrrolidinylsulfonylmethyl) indole (9b).
A solution of 35% formaldehyde (35 mL, 416 mmol) in MeOH (35 mL) and a solution of NaBH₄ (5 g, 132 mmol) in H₂O (70 mL) were added dropwise, simultaneously, at 15°C to a well-stirred solution of tryptamine 8 (8.1 g, 26 mmol) in MeOH (150 mL). The mixture was stirred at 15°C for 0.5 h, 2N aqueous HCl was cautiously added to bring the pH to 3, and the resulting mixture was stirred for 10 min. Then, the pH was adjusted to 6.5-7 with saturated aqueous NaHCO₃, MeOH was evaporated, and H₂O (50 mL) was added. The mixture was washed with EtOAc (2x150 mL), basified with K₂CO₃, and extracted with EtOAc (2x130 mL). The organic extracts were dried, filtered, and concentrated to give 9b⁴ (7.70 g, 88%) as a brown solid.


[4] Fernandez, M.-D.; Puig, C.; Crespo, M.-I.; Moragues, J. Patent ES2084560, 1994; Chem Abstr. 1996, 125, 221573.

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They use simple NaBH₄, no expensive derivate like NaBH₃CN. The 5-substitution seems not to influence the reaction in anyway.

The corresponding beta-carboline is synthesized by Pictet-Spengler reaction:

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2-Methyl-6-(1-pyrrolidinylsulfonylmethyl)-1,2,3,4-tetrahydro-b-carboline (11b).
A solution of tryptamine 8 (4 g, 13 mmol) in 35% HCHO (5 mL) and AcOH (18 mL) was refluxed for 6 h. After cooling to rt, saturated aqueous Na₂CO₃ was added, and the mixture was extracted with 95:5 CH₂Cl₂-MeOH. The residue was dissolved in THF (20 mL) and saturated aqueous Na2CO3 (20 mL). After stirring at rt overnight, the mixture was extracted with CH₂Cl₂ (2x30 mL). The organic extracts were washed with H₂O (2x20 mL), dried, Æltered, and concentrated to give beta-carboline 11b as a yellow oil (3.60 g, 87%). The oxalate precipitated on treating a solution of the base in EtOH with oxalic acid in EtOH; mp decomposed above 145°C.

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b) Another interesting point of this article is the synthesis of the indole core. The Fischer-Indole synthesis uses substituted phenylhydrazines as the key starting material. Unfortunately phenylhydrazines are not OTC, they are quite toxic and presumably carcinogenic. But the method presented offers an OTC route. An unsubstituted or 4-substituted aniline (anilines can be prepared from the corresponding benzoic acids, Post 431119 (Lego: "Aromatic carboxylic acids to anilines", Novel Discourse), for 4-hydroxyaniline one might use 4-hydroxybenzoates which are incredible cheap and commonly used as preservatives), convert it to the diazonium salt with NaNO₂ (http://www.geocities.com/dritte123/NaNO2.html (http://www.geocities.com/dritte123/NaNO2.html) and then reduce it to the phenylhydrazine with SnCl₂ (Post 355617 (Mountain_Girl: "Prep of anhydrous SnCl2 & SnCl2.H2O", Chemistry Discourse)). The phenylhydrazine is then reacted with 4-chlorobutanal diethyl acetal to tryptamine or more elegant with 4-(N,N-dialkylamino)butanal diethyl acetal to the N,N-dialkylated tryptamine.

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3-(2-Aminoethyl)-5-(1-pyrrolidinylsulfonylmethyl)-indole (8)
A solution of NaNO₂ (1.36 g, 19.7 mmol) in H₂O (8 mL) was added dropwise at -20°C to a suspension of aniline 6¹⁸ (3.5 g, 14.6 mmol) in 35% aqueous HCl (30 mL). The mixture was stirred at -20°C for 15 min and then was added at -20°C to a solution of SnCl₂ 2H₂O (16.46 g, 73 mmol) in 35% aqueous HCl (12 mL). After stirring at -20°C for 25 min and at -5°C for another 25 min period, the precipitated hydrazine 7 hydrochloride was collected by filtration and successively washed with cool H₂O and Et₂O (3.06 g, 82%). A solution of 4-chlorobutyraldehyde diethyl acetal 17 (21.8 g, 120.5 mmol) in 35% aqueous HCl (5.3 mL) and H₂O (270 mL) was stirred at rt for 1 h and added to a solution of hydrazine 7 (28.0 g, 109.6 mmol) in 35% aqueous HCl (9.8 mL), H₂O (65 mL), and MeOH (300 mL). The mixture was stirred at rt for 1 h and cooled to 0°C. The precipitated yellow solid was collected by filtration and successively washed with 9:1 H₂O-MeOH (150 mL) and cool H₂O (300 mL) to afford the intermediate hydrazone hydrochloride as an  range solid. A solution of this hydrazone and Na₂HPO₄ (12.4 g, 69.6 mmol) in H₂O (70 mL), MeOH (450 mL), and 35% aqueous HCl (9.8 mL) was refluxed overnight. MeOH was evaporated, H₂O (300 mL) was added to the mixture, and the pH was adjusted to 6.5-7 with solid Na₂CO₃. The aqueous solution was washed with CH₂Cl₂ (2x300 mL) and then saturated with Na₂CO₃, extracted with CH₂Cl₂ (3x200 mL), dried, filtered, and concentrated to give 8 (19.6 g, 58%) as a brown solid.


[12] (a) Hydrazine 13 was prepared from aniline 12^12b by diazotization followed by reduction of the resulting diazonium salt with SnCl₂ (78% overall yield). (b) Wyrick, S. D.; Hall, I. H.; Dubey, A. J. Pharm. Sci. 1984, 73, 374-377.
[17] Loftfield, R. B. J. Am. Chem. Soc. 1951, 73, 1365-1366.
[18] Sulfonamides 6 and 14 were prepared from (p-nitrophenyl)-methanesulfonyl chloride, following the procedure reported^12b for the preparation of 12, but using pyrrolidine or tert-butylamine instead of NH₃.

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yes there is a much easier way to prepare phenylhydrazines from anilines than the guess I had written above utilizing carbamic acid. Page 1556 of March's 5th cites a simple reaction between a diazonium salt and sodium sulfite.

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Antoncho: Could you please a more detailed procedure as Lego was unable to find it?