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by T. Kametani et al, HTML by Rhodium

Tryptamine w as first synthesized by means of Fischer indole cyclization of the phenylhydrazone of 4aminobutyraldehyde 2. Later, Majima and Hoshino 3 prepared it by reduction of indol-3-yl-acetonitrile w hich w as
derived from the reaction of indol-3-yl-magnesium iodide w ith chloroacetonitrile. These methods have been
superseded by the preparative sequence involving gramine methiodide 4, and by the synthesis via indol-3-ylglyoxylamides 5,6. Other methods are the lithium aluminum hydride reduction of either 3-(2-nitroethyl)-indole 7 or
3-(2-nitrovinyl)-indole 8. A synthesis by the reaction of indolylmagnesium bromide w ith ethylene imine w as also
reported 9. How ever, these methods require expensive materials and numerous steps. Now w e w ish to report
an inexpensive one-step preparation of tryptamine from L-tryptophan (1).
Thus, a suspension of L-tryptophan in forty times of
w eight of diphenylmethane w as gently refluxed under
a stream of nitrogen for 15--20 min, during w hich time
evolution of carbon dioxide w as observed. After
cooling, the clear yellow reaction mixture w as treated
w ith hydrogen chloride, and the resulting precipitate
w as collected and recrystallised to give tryptamine
hydrochloride in 60-63 % yield.
Reduction of indol-3-yl-glyoxylamide 10,11 (2) w ith a
mixture of aluminum chloride and lithium aluminum
hydride (1:1) gave tryptamine hydrochloride in ~70%
yield.

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A suspension of L-tryptophan (250 mg) in w arm diphenylmethane (10 g) w as gently refluxed in a

stream of nitrogen for 5-20 min until no more evolution of carbon dioxide w as observed. After cooling,
the clear pale yellow reaction mixture w as treated w ith a benzene solution (20 ml) saturated w ith dry
hydroge n chloride. The resulting precipitate w as collected by filtration, w ashed w ith n-hexane and
dried to afford crude tryptamine hydrochloride (223 mg, 93%) w hich w as recrystallised from
ethanol/ethyl acetate to yield tryptamine hydrochloride (151 mg, 63%) as colorless needles, mp 248249C (Ref.2, mp 246-248C).

To a suspension of lithium aluminum hydride (8 g) in tetrahydrofuran (200 ml) w as added a solution of

anhydrous aluminum chloride (28 g) in tetrahydrofuran (300 ml) dropw ise and w ith ice-cooling during
1.5 hr. To this hydride solution w as added dropw ise a solution of indol-3-yl-glyoxylamide 10,11(8 g) in
tetrahydrofuran (400 ml) during 1.5 hr. The reaction mixture w as then stirred at 20-25 for 6 hr. An
aqueous solution of 30C sodium hydroxide (400 ml) w as added to the above mixture under icecooling, and the reaction mixture w as filtered off using celite. The filtrate w as evaporated under
reduced pressure under a current of nitrogen to give a brow n residue w hich w as extracted w ith a
mixed solvent ethyl ether/methanol (95:5). Removal of the solvent gave a solid w hich w as dissolved in
ethyl ether/methanol (95:5). The resulting solution w as then treated w ith dry hydrogen chloride to
form a precipitate. Filtration, follow ed by evaporation of the filtrate to dryness, afforded tryptamine
hydrochloride: yield: 1.5 g (70%). Recrystallization from ethanol/ethyl acetate gave colorless needles,
mp 246-248C.

1. Part CDLXXX, J. Heterocyclic Chem., In Press.

2. A. J. Evins, J. Chem. Soc. 99, 270 (1911).
3. R. Maxima, T. Hoshino, Chem. Ber. 58, 324 (1925).
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J. Thesing, F. Schlde, Chem. Ber. 85, 324 (1952).

M. E. Speeter, W . C. Anthony, J. Amer. Chem. Soc. 76, 6208 (1954).
F. V. Brutcher, W . D. Vanderw erff, J. Org. Chem. 23,146 (1958).
W . E. Nolan, P. J. Hartman, J. Amer. Chem. Soc. 76, 3227 (1954).
T. Kametani, K. Fukumoto, Japan. J. Pharm. Chem. 33, 83 (1961).
R. Bucourt, J. Valls, R. Joly, US Patent 2920080 (1960); C. A. 54, 13018 (1960).
M. S. Kharash, S. S. Kane, H. C. Brow n, J. Amer. Chem. Soc. 62, 2443 (1940).
J W Baker, J. Chem. Soc. 495 (1940).

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