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Synthesis of 5-Bromo Indole

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Prep of Sodium Indoline-2-Sulfonate

50g of indole was dissolved in 100 ml of ethanol. This was added to a solution of 100g of sodium bisulfite in 300 ml of H2O. THe mixture was allowed to stir overnight and the resulting light tan solid was collected by vacuum filtration, washed w/ ether and dried. The solid was not recrystallized before the next step, and was obtained in 97% yield. mp >320 C. IR(KBr) 3480, 3263, 1489, 1211, 1174, 1041, 761, 748 cm-1. Elemental analysis and NMR not done, as IR and mp agree w/ literature. (Chem. Ber. 95, 2205 (1962))

Sodium 1-Acetyl Indoline-2-Sulfonate

(From a slightly modified procedure found in Org. Prep. Proc. Int. 17(6), 391, '85) To 30g sodium bisulfite suspended in 300 ml of acetic anhydride was added 30g of the above sodium indoline-2-sulfonate. The suspension was stirred using an overhead stirrer at 70 C for 1 hour, at which time a voluminous white solid formed, and 100 ml of acetic anhydride was added to break the slurry and facilitate stirring. The temp was then increased to 90 C for 2 hours. The suspension was allowed to cool to room temp, filtered and washed with acetic anhydride (and then ether if it pleases you). The crude, damp solid was used in the next step without further purification. A small sample dried for analysis: mp>320, IR (KBr) 3481, 3009, 1657, 1483, 1385, 1207, 1051, 966, 748 cm-1. Again, no elemental analysis deemed necessary, since mp and IR agree w/ literature.


From the same reference as above, modified somewhat. All of the acylated material from the previous step was dissolved in 150 ml of H2O at 0-5 C. To this clear yellow solution was added dropwise 40g of Bromine with stirring, keeping temp below 5 C. The solution was allowed to stir at 0-5 C for 1 hour, then allowed to come to room temp. About 10g sodium bisulfite in 30 ml H2O was then added to remove excess bromine. The solution was brought to neutral pH using 40% NaOH, keeping the temp below 30 C. The solution was allowed to stir overnight (~12 hr) at 50 C, and a light tan precipitate formed. The solution was then made basic by the addition of 40% NaOH, and allowed to stir for an additional 3 hr at 50 C. The light tan precipitate was collected by vacuum filtration, washed well with water, and air dried. Recrystallization from ethanol and water gave a beige solid that weighed 16.25g (61% yield overall). mp 86-88 C; IR(KBr) 3414, 1450, 1412, 1315, 1091, 798, 763, 503 cm-1; 1H NMR (CDCl3) 6.44-7.73(m, 5H, aromatic protons), 8.08(s, 1H, NH).

We further took this 5-bromo indole and used it to prepare 5-cyano indole, using cuprous cyanide in N-methyl-pyrrolidinone. This is also a very good way to introduce a 5-methoxy group into an indole, or possibly any number of other substituents. We were also preparing 5-aryl indoles and tryptamines using the 5-bromo indole, by way of palladium catalyzed coupling of indole 5-boronic acid.

We also attempted to prepare 5-cyano tryptamine by reaction of 5-CN indole with acetyl chloride/SnCl4 to give 3-acetyl-5-CN indole, brominating this to give the bromoacetyl compound, and then reacting this with ammonia in a parr bomb, followed by reduction. The first two steps went fine, but when the bromo compound was reacted with ammonia, the product was not the desired one, but rather 2,5-bis(5'-cyano-3'-indolyl)pyrazine. When the bromoacetyl compound was reacted with dipropylamine instead of ammonia, the dipropylaminoacetyl-5-CN-indole was isolated in acceptable yields.

The 5-cyano indole was also used to prepare 5-cyano tryptamine by an interesting method that I have not seen much use of in the literature. The oxalyl chloride method was not viable because LAH would have reduced the cyano group. Thus the indole was reacted with acrylic acid to give the indole 3-propionic acid. This was then transformed into the final tryptamine as in Synth. Comm. 23, 1103, '91.