SYNTHESIS : To a solution of 0.

50 g 4-acetoxyindole (see preparation in the

recipe for 4-HO-DET) in 4 mL Et2O, that was stirred and cooled with an external
ice bath, there was added, dropwise, a solution of 0.5 mL oxalyl chloride in 3 mL
anhydrous Et2O. Stirring was continued for 0.5 h and the intermediate
indoleglyoxylchloride separated as a yellow crystalline solid but it was not
isolated. There was then added, dropwise, a 40% solution of dimethylamine in
Et2O until the pH came to 8-9. The reaction was then quenched by the addition of
100 mL CHCl3, and the organic phase was washed with 30 mL of 5% NaHSO4
solution, with 30 mL of saturated NaHCO3, and finally with 30 mL of saturated
brine. After drying with anhydrous MgSO4, the solvent was removed under
vacuum. The residue set up as crystals and, after recrystallization from THF,
provided 0.61 g 4-acetoxyindol-3-yl-N,N-dimethylglyoxylamide (80% yield) with a
mp of 204-205 °C. Anal: C,H,N.

A suspension of 0.38 g LAH in 10 mL anhydrous THF was held in an inert

atmosphere and vigorously stirred. To this there was added, dropwise, a solution
of 0.55 g of 4-acetoxyindol-3-yl-N,N-dimethylglyoxylamide in 10 mL anhydrous
THF at a rate that maintained a gentle reflux. After the addition was complete, the
refluxing was maintained for an additional 15 min, the reaction mixture cooled to
40 °C, and the excess hydride destroyed by the addition of water diluted with a
little THF. The reaction mixture was filtered free of insoluble material under a N2
atmosphere, the resulting solids washed with THF. The filtrate and washings were
combined and stripped of solvent under vacuum. The residue was distilled in a
KugelRohr apparatus and the solid distillate recrystallized from EtOAc / hexane to
give 3-[2-(dimethylamino)ethyl]-4-indolol (4-HO-DMT, psilocin) as white crystals
which, after recrystallization from ethyl acetate / hexane, had a mp of 103-104 °C.
[Erowid Note: The Erowid Expert Network has indicated that the melting point for
psilocin should be closer to 170C than to Shulgin's 103-104C in TiHKAL. Merck
12th Edition lists the melting point for psilocin as 173-176C (plates from
methanol). (Jan 16, 2013)] The final weight was 0.23 g (yield 56%). IR (in cm-1):
686, 725, 832, 991, 1040 and 1055; the OH stretch is at 3240. MS (in m/z):
C3H8N+ 58 (100%); parent ion 204 (15%); indolemethylene+ 146 (3%); 159 (2%).

Most of the early syntheses of psilocin and psilocybin employ the O-benzyl ether
as a protecting group. This provides more stability to the chemical intermediates,
but also requires the additional step of reductive debenzylation. The flow chart of
this process is: conversion of 4-hydroxyindole to 4-benzyloxyindole via the
sodium salt, with benzyl chloride; the conversion of this with oxalyl chloride to 4-
benzyloxyindole-3-glyoxylchloride; the conversion of this to 4-benzyloxy-3-(N,N-
dimethyl-glyoxamide with anhydrous dimethylamine; the conversion of this to 4-
benzyloxy-N,N-dimethyltryptamine with LAH in dioxane; and finally the conversion
of this to 4-HO-DMT (psilocin) with hydrogen with a Pd catalyst on Al2O3. The
phosphate ester, psilocybin, requires two additional steps: the conversion of 4-
HO-DMT (as the sodium salt) to 4-(O,O-dibenzylphosphoryloxy)-N,N-
dimethyltryptamine, with dibenzyl chlorophosphonate, followed by the catalytic
removal of the benzyl groups with hydrogen and Pd on Al2O3 to give the
phosphate ester of 4-HO-DMT (psilocybin). This product is much more stable in
air than psilocin, and is water soluble. The yields of this conversion are, however,
very bad, often less than 10%, and the two products appear to be
pharmacologically equivalent. Further, I have heard that the phosphorylating
agent dibenzyl chlorophosphonate must always be used in solution as it is quite
unstable as a pure reagent. The fingerprint infra-red spectrum for psilocybin
shows (in cm-1): 752, 789, 806, 858, 925 and the P=O stretch at 1110; the acidic
OH stretches are broad peaks at 2400, 2700 and 3200. The mass spectrum is
identical to that of psilocin.