A solution of 110 g p-dimethoxybenzene and 102 g valeric acid in 168 g polyphosphoric acid was heated on the steam bath for 3 h, giving a deep red homogeneous solution. This was poured into 1 L H2O with good stirring. The strongly acidic, cloudy suspension was extracted with 3×200 mL CH2Cl2, the extracts pooled, washed with 4×150 mL 5% NaOH, and finally once with dilute HCl. The solvent was removed under vacuum, and the residual amber oil cooled overnight at 0 °C. Some 30 g of crystalline, unreacted dimethoxybenzene were removed by filtration, and the 85 g of residual oil distilled at the water pump. Another 15 g of di-methoxybenzene came over as an early cut, but the fraction boil-ing at 184-192 °C (mostly 188-192 °C) weighed 53.0 g and was reasonably pure 2,5-dimethoxyamylophenone. The reaction of the acid chloride of valeric acid with p-dimethoxybenzene and anhydrous AlCl3 in CH2Cl2 (parallel to the preparation of the butyrophenone analog, see DOBU) gave an inferior yield (23.2 g from 92 g dimethoxybenzene), but did provide a sizeable sample (12.2 g) of 2-hydroxy-5-methoxyamylophenone from the basic washes of the crude reaction mixture. This pale yellow solid, after recrystallization from MeOH, had a mp of 62-62.5 °C. Anal. (C12H16O3) C,H.
To 360 g mossy zinc there was added a solution of 7.2 g mercuric chloride in 200 mL warm H2O, and this was swirled periodically for 2 h. The H2O was drained off, and the amalgamated zinc added to a 2 L three-neck round-bottomed flask, treated with 200 mL concentrated HCl, and heated with an electric mantle. A solution of 53.0 g of 2,5-dimethoxyamylophenone in 107 mL EtOH containing 30 mL concentrated HCl was added drop-wise over the course of 4 h accompanied by 330 mL of concentrated HCl added batchwise over this same period. The mixture was held at reflux overnight and, after cooling, diluted with sufficient H2O to allowed CH2Cl2 to be the lower phase. The phases were separated, and the aqueous phase was extracted with 2×200 mL additional CH2Cl2. These organic phases were combined, washed first with 5% NaOH and then with H2O, and the solvent removed under vacuum. Distillation at the water pump yielded two fractions. The first distilled from about 100-130 °C, weighed 8.8 g, had a faint smell of apples and fennel, and was free of a carbonyl group in the infra-red. It proved to be only 50% pure by GC, however, and was discarded. The major fraction was a pale amber oil distilling between 152-170 °C and was substantially free of smell. It weighed 18.9 g, and was (by GC) 90% pure 2,5-dimethoxy-(n)-amylbenzene.

A mixture of 36.3 g POCl3 and 40.9 g N-methylformanilide was allowed to incubate for 0.5 h. To this there was then added 18.5 g of 2,5-dimethoxy-(n)-amylbenzene and the mixture heated on the steam bath for 2 h. This mixture was poured into a large quantity of H2O and stirred overnight. The black oily product was extracted with 3×100 mL CH2Cl2, and the extracts combined and stripped of solvent under vacuum. The black residue was distilled at 180-205 °C at 20 mm/Hg to give 12.5 g of a pale amber oil that slowly set up to a crystalline mass. An analytical sample was recrystallized from MeOH to provide 2,5-dimethoxy-4-(n)-amylbenzaldehyde with a mp of 25-26 °C. Anal. (C14H20O3) H; C: calcd, 71.16: found, 71.92, 71.74.

A solution of 12.3 g 2,5-dimethoxy-4-(n)-amylbenzaldehyde in 50 mL acetic acid was treated with 4.0 g anhydrous ammonium acetate and 12 mL nitroethane. This mixture was heated on the steam bath for 4 h, then poured into a large quantity of H2O. This was extracted with 3×200 mL CH2Cl2, the extracts washed with H2O, and the solvent removed to give a deep red oil that, on standing in the refrigerator, slowly set to a crystalline mass weighing 13.5 g. An analytical sample was recrystallized from MeOH to provide 1-(2,5-dimethoxy-4-(n)-amylphenyl)-2-nitropropene as fine yellow microcrystals with a mp of 44 °C sharp. Anal. (C16H23NO4) C,H,N.

To a gently refluxing suspension of 10 g LAH in 500 mL anhydrous Et2O under a He atmosphere, there was added by 13.2 g 1-(2,5-dimethoxy-4-(n)-butyl-phenyl)-2-nitropropene by allowing the condensing ether drip into a Soxhlet thimble containing the nitrostyrene which effectively added a warm saturated solution of it dropwise to the reaction mixture. Refluxing was maintained for 18 h, and the cooled reaction flask stirred for several additional days. The excess hydride was destroyed by the cautious addition of 1 L 8% H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and the aqueous layer was washed with an additional 2×100 mL Et2O. Removal of the solvent from the organic phase and washings provided 4.7 g of a thick red oil that was discarded. The aqueous phase was then extracted with 2×200 mL CH2Cl2 which actually removed the product as the sulfate salt. This organic phase was washed with 2×100 mL 5% K2CO3 (removing the H2SO4) and with the evaporation of the solvent there was obtained 6.2 g of an oily amber residue. This was dissolved in 200 mL Et2O and saturated with anhydrous HCl gas. Fine white crystals of 2,5-dimethoxy-4-(n)-amylamphetamine hydrochloride (DOAM) separated, were removed by filtration, Et2O-washed and air dried, and weighed 5.2 g. The mp of 136-139 °C was increased to 145-146 °C by recrystallization from CH3CN. Anal. (C16H28ClNO2) C,H,N.

DOSAGE: greater than 10 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 10 mg) There was a clear threshold that in no way interfered with my day’s activities. I was quite gay and voluble at lunch and bubbled on into the afternoon with puns and high spirits. There may have been a little motor incoordination as noted in handwriting, and there was a strange tenseness during driving. There were no sequelae, there was no trouble sleeping, and with this potency way down from the lower homologues, I have no pressing desire to take this compound to a higher dose.

EXTENSIONS AND COMMENTARY: The actual procedure that was published for the isolation of this final amine was a different one, one that would certainly work, but which was based on the procedures tried and proven with the lower homologues. The process described above is just a bit bizarre (a sulfate salt extracting into methylene chloride) but it was the actual thing that was done. The work was started towards two additional compounds but these never got past the first „ketone and phenol“ stage. p-Dimethoxybenzene was brought into reaction with n-caproic acid with polyphosphoric acid (aiming towards 2,5-dimethoxy-4-(n)-hexylamphetamine, DOHE) but this was dropped when DOAM proved to be down in potency. And the reaction between p-dimethoxybenzene and benzoyl chloride with anh. aluminum chloride went well (aiming towards 2,5-dimethoxy-4-benzylamphetamine, DOBZ). A goodly amount of the phenol (2-hydroxy-5-methoxybenzophenone) was obtained as fine yellow crystals, but this line of inquiry was also dropped.

The preparation of DOAM was, as a matter of fact, the last of the homol-ogous series of compounds actually completed, which stemmed from the original discovery of DOM. The „Ten Classic Ladies“ concept was mentioned under ARIADNE, and the adding of a methyl group in the place of a hydrogen atom at the 4-position-methyl led to the synthesis of Ms. HECATE and gave rise to DOET. The whole series of methyl-ethyl-propyl-butyl-amyl compounds was appealing to me, in that the potency seemed to increase initially as the chain got longer, and then it abruptly dropped off. Wouldn’t it be nice, I thought, if I could interest some pharmacologist in looking at this tight set of drugs with some animal model, to see if there is some neurotransmitter activity that would show a parallel action.

I learned of a curious young researcher in Washington who had an elegant procedure for measuring serotonin agonist action using the (otherwise) discarded sheep umbilical artery strips. These become available each year at lambing time, do not cost the life of anything, and require very little compound. He assayed my compounds and, lo and behold, the serotonin activity also went through a maximum in the middle of this series. We published a short paper to this effect, which served as a excellent vehicle to get the cogent human data into the scientific literature.

I have never understood the reasons that there might be connection between the twitching of a umbilical artery in a sheep and the appearance of an insight in the mind of man. And, I have never personally met this pharmacologist. Some day, I hope to do both.

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