Thursday, 8 November 2012


To a solution of 0.50 g 4-acetoxyindol 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. 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 allized 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. 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.