Pihkal

by Alexander Shulgin

  Anal. (C11H13NO4) C,H,N. This nitrostyrene has been periodically available commercially from a number of sources.

  A solution of 17.0 g of 1-(2,5-dimethoxyphenyl)-2-nitropropene was prepared in 500 mL anhydrous Et2O. This solution was added slowly to a well-stirred suspension of 12.0 g LAH in 700 mL anhydrous Et2O. The mixture was then brought up to a reflux and maintained there for 20 h, cooled with an external ice bath, and the excess hydride destroyed by the cautious addition of H2O. Finally, a total of 500 mL H2O was added, followed by the addition of 300 g potassium sodium tartrate, and sufficient aqueous NaOH to bring the pH above 9. The two phases were separated, and the ether phase dried by the addition of anhydrous MgSO4. The drying agent was removed by filtration, and the clear filtrate saturated with a stream of anhydrous HCl gas. The formed crystals of 2,5-dimethoxyamphetamine hydrochloride (2,5-DMA) were removed by filtration, washed with anhydrous Et2O, and dried to constant weight of 16.3 g. Recrystallization from EtOH gave an analytical sample with a mp of 114-116 !C. The hydrobromide salt is reported to melt at 129-131 !C.

  DOSAGE: 80 - 160 mg.

  DURATION: 6 - 8 h.

  EXTENSIONS AND COMMENTARY: The qualitative information on 2,5-DMA is very sparse. I was up to a 1+ with 80 milligrams of the hydrochloride, and since it appeared to be totally a physical trip with tremors and some cardiovascular push and nothing of a sensory nature, I chose to explore it no further. A report from South America found the intoxication to be largely pleasant (this, at 75

  milligrams), with an enhanced interest in one's surroundings, but no perceptual changes, no overt stimulation, and no gross physiological effects other than a slight mydriasis (dilation of the pupils). I have also been told of a single trial of 250 milligrams of the tartrate (this is equivalent to somewhere in the 150-200 milligram range of the hydrochloride salt, depending upon the acid/base ratio of the tartrate salt) with some RspeedyS effects but still no sensory changes. A seizure of capsules reported by the drug law enforcement authorities some 20 years ago found that each contained some 200

  milligrams of the hydrobromide salt. This is equivalent to 170

  milligrams of the hydrochloride salt, and suggests that level may be an effective dosage.

  An intriguing, but little studied, analogue of 2,5-DMA is the compound with methyls in place of the methoxyls. 2,5-Dimethylamphetamine has been looked at, in man, as a potential anorexic, but there is little effect even at 150 milligrams. The 3,4-isomer, 3,4-dimethylamphetamine or xylopropamine, is an adrenergic agent and it has been found to be an analgesic in man at as little as 10

  milligrams. This was assayed, rather remarkably, by attaching electrodes to the tooth fillings of the experimental subjects. But with this base, cardiovascular effects were not observed until doses of about 100 milligrams were administered, and toxic effects (nausea and vomiting) were reported at 150 milligrams. There was no suggestion of anything psychedelic.

  All three isomers of monomethylamphetamine have also been looked at in man. The ortho- and meta-isomers, 2-methyl- (and 3-methyl- ) amphetamine are weak anorexics. At doses of up to 150 milligrams orally, there were signs of stimulation noted Q talkativeness and loss of appetite. The para-isomer, 4-methyl-amphetamine or Aptrol, is more potent. At 75 milligrams (orally, in man) there is clear adrenergic stimulation, and at twice this dosage there are signs of mild toxicity such as salivation, coughing and vomiting.

  There is a mystery, at least to me, concerning the commercial production of 2,5-DMA. At regular intervals, there is a public announcement of the production quotas that are requested or allowed by the Drug Enforcement Administration, for drugs that have been placed in Schedules I or II. In the Schedule I category there are usually listed amounts such as a gram of this, and a few grams of that. These are probably for analytical purposes, since there are no medical uses, by definition, for drugs in this Schedule. But there is a staggering quantity of 2,5-DMA requested, regularly. Quantities in the many tens of millions of grams, quantities that vie with medical mainstays such as codeine and morphine. I have heard that this material is used in the photographic industry, but I have no facts. Somewhere I am sure that there is someone who has to keep a lot of very careful books!

  In the area of psychedelic drugs, the value of 2,5-DMA is mainly in its role as a precursor to the preparation of materials that can come from a direct electrophilic attack on the activated 4-position. These uses can be found under things such as DOB and DOI and DON. The radio-halogenation of N-substituted homologues of 2,5-DMA with hypoiodite or hypofluorite is part of an extensive study underway in the search for radio-labeled brain blood flow agents. The rationale for this work is to be found in the commentary under IDNNA. In essence it has been found that the N-substitution or N,N-disubstitution of 2,5-DMA where the 4-position is unsubstituted and thus available for the introduction of a radioactive nucleus can give rise to potentially useful drugs. Most of these 2,5-dimethoxy exploratory compounds were made by the reductive alkylation of 2,5-dimethoxy-4-(radio)iodophenylacetone, using various mono or dialkyl amines. This, too, is described under IDNNA.

  However, the study of various direct iodinations and fluoridations that would have the N,N-dimethyl substitution on the amphetamine nitrogen atom, would require the 4-proteo- analogue, and this was made from the above nitrostyrene. A solution of the above nitrostyrene, 22.3 g 1-(2,5-dimethoxyphenyl)-2-nitropropene in 100 mL acetic acid was added to a suspension of elemental iron in acetic acid (45 g in 250 mL) and worked up with water and base washing to give, after distillation at 92-106 !C at 0.35 mm/Hg, 13.8 g 2,5-dimethoxyphenylacetone as a pale yellow oil. This underwent reductive amination with dimethylamine hydrochloride in MeOH solution, using sodium cyanoborohydride, to give the target compound 2,5-dimethoxy-N,N-dimethylamphetamine oxalate with a melting point of 133-134 !C (4.6 g ketone gave 1.38 g of salt). Anal. (C15H23NO6) C,H.

  It has also been prepared by the N,N-dimethylation of 2,5-DMA directly, with formaldehyde and formic acid. This has been called 2,5-DNNA, or IDNNA without the RI.S This intermediate, 2,5-DNNA, underwent direct radioiodination with labeled iodine monochloride in the presence of perchloric acid to give IDNNA with a 40% incorporation of isotope. Reaction with labeled acetyl hypofluorite, on the other hand, gave only a 2% in-corporation of the radio-isotope. This latter compound is, chemically,

  4-fluoro-2,5-dimethoxy-N,N-dimethylamphetamine and, using the reasoning suggested above and with IDNNA, might best be encoded FDNNA.

  The 2,5-dimethylamphetamine analogue mentioned above was also explored in this IDNNA concept. The commercially available 2,5-dimethylbenzaldehyde was converted to the nitrostyrene with nitroethane (1-(2,5-dimethylphenyl)-2-nitropropene, yellow crystals with a melting point of 24.5-25.5 !C) which reacted with elemental iron in acetic acid to give the ketone 2,5-dimethylphenylacetone (boiling at 140-150 !C at 0.4 mm/Hg). Reductive amination with dimethylamine and sodium cyanoborohydride gave 2,5-DMNNA (2,5,N,N-tetramethylamphetamine) as a clear oil with a boiling point of 115-125 !C at 0.35 mm/Hg. It gave poor yields of the 4-fluoro analogue with acetyl hypofluorite.

  All of these latter materials remain unevaluated in man.

  55 3,4-DMA; 3,4-DIMETHOXYAMPHETAMINE

  SYNTHESIS: A solution of 33.2 g of veratraldehyde in 15.0 g nitroethane was treated with 0.9 g of n-amylamine and placed in a dark place at room temperature. In a day or so, separated H2O was apparent and, after a couple of weeks, the mixture completely solidified. The addition of 50 mL EtOH and heating effected complete solution and, on cooling, this provided 1-(3,4-dimethoxyphenyl)-2-nitropropene as yellow crystals, 29.0 g, with mp of 70-71 !C. The more conventional reaction scheme, 6 h heating of a solution of the aldehyde and nitroethane in acetic acid with ammonium acetate as catalyst, gave a much inferior yield of product (33.2 g gave 14.8 g) of the same purity. Recrystallization from MeOH increased the mp to 72-73 !C.

  To a refluxing suspension of 7 g LAH in 600 mL anhydrous Et2O, stirred and under an inert atmosphere, there was added 7.5 g 1-(3,4-dimethoxypheny
l)-2-nitropropene by allowing the returning condensed ether to leach out the material as a warm solution from a Soxhlet thimble. Following the completion of the addition of the nitrostyrene, refluxing was maintained for 24 h, and the reaction mixture allowed to stand several days at room temperature. The excess hydride was destroyed by the cautious addition of 500 mL H2O

  containing 40 g H2SO4, and the phases were separated. The aqueous phase was washed with both Et2O and CH2Cl2. There was then added 200

  g potassium sodium tartrate, and the pH brought above 9 by the addition of aqueous NaOH. This clear solution was extracted with 3x150 mL CH2Cl2, the extracts were pooled, and the solvent removed under vacuum to give a residual oil. This was dissolved in Et2O, saturated with anhydrous HCl gas, and the resulting solids removed by filtration. Recrystallization from 10 mL acetone gave 1.35 g 3,4-dimethoxyamphetamine hydrochloride (3,4-DMA) as beautiful white crystals with a mp of 144-145 !C.

  DOSAGE: a few hundred milligrams.

  DURATION: unknown.

  QUALITATIVE COMMENTS: (with 70 mg i.v.) [One patient received 0.004

  mM/Kg of the hydrochloride salt intravenously and exhibited only slight increase in psychiatric symptoms; a comparable dosage in a second individual also elicited only insignificant changes.]

  (with 700 mg i.v.) [When one of these patients was reinjected at a later date with approximately 0.04 mM/Kg of 3,4-DMA a definite Tmescaline-likeU state was induced. The symptoms included colored hallucinations of geometric figures and occasional structured forms.

  The other individual experienced visual distortions, notable after-imagery, feelings of unreality, and paranoid ideas. Marked mydriasis and gross body tremors also occurred but apparently no hallucinations were experienced.]

  EXTENSIONS AND COMMENTARY: These RQualitative CommentsS are not explicit quotations from people who had taken 3,4-DMA. They are written descriptions by the observers who had given 3,4-DMA to psychiatric patients. This is one of the most outrageous chapters in the books on military medicine. The chemical warfare group within the U.S. Army explored many potential psychedelics by administering them to innocent patients with not even a thought of obtaining informed consent. These experiments took place at the New York State Psychiatric Institute (amongst other places) in the early 1960Us. The Edgewood Arsenal code name for 3,4-DMA was EA-1316. A few non-military studies have indicated that 3,4-DMA is orally active at 160 milligrams, and so probably its potency by this more conventional route would fall midway between that of mescaline and of MDA. The 3-methoxy-4-other-than-methoxy things (such as hydroxy, ethoxy, allyloxy and methyl) are mentioned in the recipe for MEPEA. The alpha-ethyl homologue of 3,4-DMA,

  2-amino-1-(3,4-dimethoxyphenyl)butane, and of other DMA's are discussed under the recipe for ARIADNE.

  There are a total of six possible amphetamine molecules with two methoxyl groups attached. The 3,4-orientation has always been the most appealing to the life scientists as this is the positional substitution pattern found in the natural neuro-chemicals dopamine, norepinephrine and epinephrine. These latter two are called noradrenalin and adrenalin in England. Two adjacent hydroxy groups represent the catechol in the well known word catecholamines. You might read in a textbook, RThis is where nature placed the groups when she put the compounds in our brains. So that is where the groups might be the most interesting in a psychedelic.S Why? I have never understood this kind of reasoning. If a possible psychedelic has just the exact oxygen positioning of a neurotransmitter, then, voila, that's why it is active. And if a possible psychedelic has some positioning of these oxygen atoms that is different than that of a neurotransmitter? Then voila again. That's why it is active. Both sound equally reasonable to me, and neither one even begins to address the fundamental question, how do the psychedelic drugs do what they do? A study in the human animal of the intimate effects of one of these neurotransmitter analogues might bring us a little bit closer to answering this fundamental question. But maybe it wouldnUt, after all. Nothing has made much sense so far! Anyway, 3,4-DMA is one of the ten essential amphetamines that can, in theory, arise from the ten essential oils of the spice and herb trade. In this case, the origins are methyl eugenol and methyl isoeugenol.

  Two of these RdifferentS isomers, 2,4-DMA and 2,5-DMA, have already been discussed in their own separate recipes. And the remaining three of the six possible DMA's that are RdifferentS have been made and studied pharmacologically in animals but not in man. These are the 2,3-DMA, 2,6-DMA and the 3,5-DMA isomers. The products of their reaction with elemental bromine are discussed under META-DOB.

  Both the 2,6- and the 3,5-isomers, as the N,N-dimethyl homologues, have been looked at as potential radio-halogen recipients in the search for positron-emitting brain blood-flow indicators, as discussed in the recipe for IDNNA. Both were made from the appropriate nitrostyrene via the corresponding phenylacetone.

  The 2,6-isomer was derived from 2,6-dimethoxybenzaldehyde. This, in nitroethane and ammonium acetate, gave the nitrostyrene as canary-yellow crystals from MeOH that melted at 101.5-102.5 !C.

  Elemental iron in acetic acid converted this nitrostyrene to 2,6-dimethoxyphenylacetone (a water-white oil with boiling point of 95-105 !C at 0.4 mm/Hg. Anal. (C11H14O3) C,H) and reductive amination with dimethylamine and sodium cyanoborohydride gave 2,6-dimethoxy-N,N-di-methylamphetamine perchlorate (2,6-DNNA) with a melting point of 109-110 !C. This base was readily fluorinated with 18F acetylhypofluorite and iodinated with chloramine-T-oxidized 122I iodide ion. It was also halogenated with (non-radioactive) bromine and iodine monochloride to give the corresponding 3-bromo-(and 3-iodo)-2,6-dimethoxy-N,N-dimethylamphetamines but these, in turn, did not react with radioactive acetyl hypofluorite.

  The 3,5-isomer followed precisely the same flow sheet.

  3,5-Dimethoxybenzaldehyde gave the nitrostyrene (with a melting point of 87-88 !C), the phenylacetone (with a boiling point of 110-130 !C at 0.3 mm/Hg) and the product 3,5-dimethoxy-N,N-dimethylamphetamine perchlorate (3,5-DNNA) with a melting point of 100-101 !C. This also reacted readily with 18F acetylhypofluorite and 122I-hypoiodite.

  Several alpha-ethyl homologues of these compounds have also been discussed in the recipe for ARIADNE.

  56 DMCPA; 2-(2,5-DIMETHOXY-4-METHYLPHENYL)CYCLOPROPYLAMINE

  SYNTHESIS: To a solution of 25 g 2,5-dimethoxy-4-methylbenzaldehyde (see the recipe for 2C-D for the preparation) and 29.2 g malonic acid in 50 mL anhydrous pyridine, there was added 2 mL piperidine and this was heated on the steam bath for several h. The mixture was added to a solution of 125 mL concentrated HCl in 500 mL H2O at 0 !C, and the solid product that was formed was removed by filtration, and washed with H2O. Recrystallization from aqueous EtOH yielded 31 g 2,5-dimethoxy-4-methylcinnamic acid with a mp of 163-166 !C. Anal.

  (C12H14O4) C,H.

  In a cooled high-pressure reaction vessel there was placed a suspension of 30 g 2,5-dimethoxy-4-methylcinnamic acid in 150 mL

  liquid isobutene. This was treated dropwise with 0.6 mL concentrated H2SO4, then sealed and brought to room temperature. After 48 h shaking, the vessel was cooled again to -10 !C, opened, and poured into 200 mL of 10% Na2CO3. This was extracted with hexane, the pooled extracts washed with H2O, and the solvent removed to yield 17.0 g of (t)-butyl 2,5-dimethoxy-4-methylcinnamate as an amber oil. Anal.

  (C16H22O4) C,H.

  The cyclopropane ester was prepared by the reaction between 16 g (t)-butyl 2,5-dimethoxy-4-methylcinnamate and dimethylsulfoxonium methylide, prepared as described in the Kaiser reference in the acknowledgements. Hydrolysis of this ester gave 53%

  trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropanecarboxylic acid which, after recrystallization from a MeOH/H2O mixture, had a mp of 136 !C. Anal. (C13H16O4) C,H.

  A suspension of 4 g of

  trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropanecarboxylic acid in an equal volume of H2O, was treated with sufficient acetone to effect complete solution. This was cooled to 0 !C and there was added, first, 2.0 g triethylamine in 35 mL acetone, followed b
y the slow addition of 2.5 g ethyl chloroformate in 10 mL acetone. This was stirred for 0.5 h, and then there was added a solution of 1.7 g NaN3

  in 6 mL H2O, dropwise. After 1 h stirring at 0 !C, the mixture was quenched by pouring into H2O at 0 !C. The separated oil was extracted with Et2O, and extracts dried with anhydrous MgSO4. Removal of the solvent under vacuum gave a residue of the azide, which was dissolved in 10 mL anhydrous toluene. This solution was heated on the steam bath until the nitrogen evolution was complete, and the removal of the solvent under vacuum gave a residue of crude isocyanate as an amber oil. This intermediate isocyanate was dissolved in 5.4 g benzyl alcohol and the reaction mixture was heated on the steam bath for 6 h.

  The excess benzyl alcohol was removed by distillation, yielding trans-2-(2,5-dimethoxy-4-methylphenyl)carbobenzoxyamidocyclopropane as a crystalline residue. This was recrystallized from an EtOAc/hexane mixture to give 6.13 g of a crystalline product with a mp of 107-108

  !C. Anal. (C20H23NO4) C,H,N.

  A solution of 1.5 g

  trans-2-(2,5-dimethoxy-4-methylphenyl)carbobenzoxyamidocyclopropane in 120 mL MeOH containing 200 mg 10% Pd/C was shaken under hydrogen gas at 35 psig for 45 min. The solution was filtered through celite, and a sufficient amount of a solution of 5% HCl in EtOH was added to the filtrate to make it acidic. Removal of all volatiles under vacuum gave a solid residue that was recrystallized from an EtOH/ether mixture to give 0.98 g of

  trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine hydrochloride (DMCPA) as white crystals with a mp of 210-211 !C.

  DOSAGE: 15 - 20 mg.