Mescaline and Friendsby Michael Valentine Smith
Mescaline and related alkaloids are found in varying amounts in cacti of the genera Lophophora, Cymnacalycium, Stensonia, Mammillaria, Ariocarbus, Obuntia, Trichocereus, Pelecyphora, and probably others. Members of the Native American Church do quite well with the dried cactus, but extraction of mescaline is desirable since the pure compound seems to produce fewer unpleasant side effects (e.g., nausea). For an excellent review on the occurrence and chemistry of the mescaline type compounds, see JPS 59, 1699(1970) (cf. JPS 60,655(1971)). Various species of these cacti occur in southwestern U.S. as well as Central and South America and have been used by the Aztecs and others for millennia. For a good review of peyote see Lloydia 36, 1-58(1973).
Extraction of Mescaline from Cactus JACS 88,4218( 1966), Lloydia 29,318(1966)
Dry and grind the top of the cactus and add 50 g to 250 ml methanol and let soak one day. Filter and add 100 ml 1N HCl to the wet powder and let stand about two hours. Meanwhile, evaporate in vacuum the methanol. Filter the HCl solution until clear and add to the residue remaining from the methanol. Make pH about 7 with 2N KOH and add 100 ml CHCl3. Shake in separatory funnel and separate the bottom CHCl3 layer. Add 40 ml water to the CHCl3 and shake in separatory funnel. Dry and evaporate in vacuum the CHCl3 layer to get the mescaline (and other compounds).
The most detailed directions for cactus extraction are contained in PSYCHEDELIC GUIDE TO THE PREPARATION OF THE EUCHARIST by R. Brown, obtainable for $5.50 from L.S.l. Co., PO Box 4374, Austin, TX 78765.
Another source pressure cooked the peyote in acidic water 15 minutes at 15 lbs. and poured off the liquid. This process was repeated 5 more times and the combined water extracts evaporated slowly to a tar which is cooled until able to be formed into small pills. The pills are dipped in Salol (phenyl salicylate), which has been liquefied by heating, and allowed to dry. This forms an enteric coating which is said to allow ingestion without nausea. Others merely put the tar in gelatin capsules. Either way the nausea of whole peyote is greatly diminished. Three or four tabs are supposed to have the impact of 15-20 buttons.
Methoxyphenethylamines and Derivatives
Of the nineteen possible methoxyphenethylamines, only three are known to be psychedelic in man at reasonable doses. These are the 3,4,5-trimethoxy-(mescaline), 2,3,4,5 and 2,3,4,5,6 compounds. There are, however, a vast number of possible psychedelic derivatives with methyl, ethyl, Br, and other groups replacing methoxy groups. In addition, innumerable amphetamine derivatives which closely resemble mescaline in their structure and psychedelic properties have been synthesized. This similarity can be seen in the structures of mescaline and 3,4,5-trimethoxyamphetamine.
These amphetamine derivatives have the advantage that they are almost all more active than mescaline, STP being about 80x more active (i.e., requiring only about 5 mg as contrasted with about 400 mg for mescaline), and that they are often easier to synthesize. They do, however, seem to produce somewhat more of the effects of speed (e.g., anxiety, restlessness, sweating) than mescaline. The methylenedioxy compounds, on the other hand, produce some of the mildest trips of any psychedelic.
2-5,dimethoxy-4-Br-amphetamine (prepared by bromination of 2,5-dimethoxy-amphetamine -- see JCS 200(1953)) is about ten times more active than STP but it produces a trip similar to that of MDA and is not truly hallucinogenic. The phenethylamine analogs of this compound and of STP are ten times less potent than the corresponding amphetamines and produce only MDA type effects without the intense sensory alterations. Beta-hydroxy-3,4-methylenedioxyphenylethyl amine is said to be a very fine trip.
When the amino group of amphetamine is methylated, one gets methamphetamine which is considerably more stimulating. The corresponding hallucinogenic analogs of methamphetamine have not yet been shown to have any special stimulating properties, having on the contrary less potency than the unmethylated forms (see JMC 13,134(1970)), but human tests should be done (preliminary results show these compounds to be very pleasant).
N-methyl-MDA is extremely pleasant, producing more euphoria than cocaine, lasting much longer and having a very easy down. N,N-dimethylation or N-ethylation diminish activity drastically and the latter appears to have sedative effects. The methylenedioxy compounds are generally free of marked visual changes, allow considerable voluntary control of the experience and are more potent than the dimethoxy counterparts.
It is probably best to avoid p-methoxyamphetamine (PMA) and 2,5-dimethoxy-4-methylamphetamine (STP), the former because it seems to have a high toxicity and the latter because it lasts too long (e.g., 24 hours for a minimum dose). Other 4-alkyl amphetamines also seem to be toxic. A number of apparent fatalities due to MDA have been noted, but the reports usually involve very large amounts, often in combination with other drugs (e.g., 7 g MDA plus barbiturates) and screening for other, more toxic drugs (in particular, PMA) has not been done.
These amphetamine analogs can be produced by using the appropriately substituted benzaldehyde in place of 3,4,5-triù methoxy-benzaldehyde, and nitroethane in place of nitro-methane in the aldehyde method for mescaline synthesis (using nitropropane, etc., to give a longer chain results in less activity). However, easier synthetic routes from the naturally occurring (therefore cheap and commercially available) ring substituted propenylbenzenes are given here.
The following table lists common names, position of ring substitution, and approximate activity of the amphetamine derivatives for some readily available allyl and propenyl benzenes (see J. Chromatography 30,54(1967) for further information on these compounds). Activity is relative to mescaline which equals 1 (an activity of 12 means a dose of about 25 mg). Parentheses indicate a methylenedioxy bridge; other substituents are methoxy groups.
Amphetamines from Allylbenzenes JACS 91,5648(1969)
To a cooled and stirred solution of 100 ml acetonitrile and 64.8 g mercuric nitrate, add slowly 0.2M of the allylbenzene (keep temperature below 30ø). Stir one hour at room temperature, cool and add 200 ml 3N NaOH, then 200 ml 0.5M NaBH4 in 3N NaOH. After one hour saturate the water layer with NaCl and extract with ether. Dry and evaporate in vacuum the extract to get the N-acetyl-amphetamines. This procedure may not work with the propenylbenzenes. If it is desired to remove the N-acetyl group see CJC 51,1407 (1973).
Amphetamines from Propenylbenzenes CA 52,11965(1958)
Use of N-methyl-formamide in place of formamide will give the corresponding N-methyl-amphetamine which is nicer. Exemplified for 3,4-methylenedioxyamphetamine (MDA). To a cooled mixture of 34 g 30% H202 and 150 g formic acid, add dropwise a solution of 32.4 g (0.2M) isosafrole in 120 ml acetone (keep temperature below 40ø). Let stand about twelve hours and evaporate in vacuum. Add 60 ml methanol and 360 g 15% sulfuric acid to the residue and heat on water bath three hours. Cool, extract with ether or benzene and evaporate in vacuum the extract to give 20 g 3,4-methlenedioxybenzyl-methyl ketone (I) (can distill 115/2). Add 23 g (I) to 65 g formamide and heat at 190ø for five hours. Cool, add 100 ml H2O, extract with benzene and evaporate in vacuum the extract. Add 8 ml methanol and 75 ml 15% HCl to residue, heat on water bath two hours and evaporate in vacuum (or basify with KOH and extract the oil with benzene and dry, evaporate in vacuum) to get about 11 g MDA. In this, as in the other syntheses, either the cis or trans (alpha or beta) propenylbenzenes (or a mixture) may be used.
Amphetamines from Probenylbenzenes JMC 9,445(1966)
If the allyl isomer is at hand, it must first be converted to the propenyl as follows (CJC 43,3437(1965)): Add equal weights of the allyl compound and KOH flakes, and absolute ethanol and heat on steam bath or reflux for twenty-four hours; dry and evaporate in vacuum or add two times the volume of water and extract with ether or methylene chloride and dry, evaporate in vacuum (recrystallize-hexane).
0.034M propenylbenzene in a mixture of 3.3 g pyridine and 41 g dry acetone is cooled to 0ø and 6.9 g tetranitro-methane added over one minute with vigorous stirring, and stirring continued for two minutes. Add 2.2 g KOH in 40 ml water, add more water and extract the nitroprpene with methylene chloride and dry, evaporate in vacuum (recrystallize-methanol). The nitropropenes (which seem to have little activity themselves) can be reduced to the active amphetamines with lithium aluminum hydride or Zn-Hg as described later, or reduced by another method (hydroboration, hydrogenation, Na-ethanol, electrolytic, etc.).
Mescaline and Amphetamines from Styrenes and Propenylbenzenes JACS 86,3565(1964)
The yield of mescaline should be about 50%; that for amphetamines will vary. 0.1 M of ring substituted styrene or propenylbenzene in 30 ml tetrahydrofuran in 1/2 L flask. Flush with N2 and add 33 ml 1 M borane in tetrahydrofuran (see procedure below for preparation). Stir one hour, add 3 ml water and 50 ml 3N NaOH, and then 215 ml 0.31 M fresh chloramine solution (prepared by treating dilute aqueous NH4OH with Na hypochlorite at Oø; see BER 40,4586 (1907)). Keep at room temperature one hour, acidify with HCl, extract with ether, basify with NaOH and extract with ether and dry, evaporate in vacuum (or just basify and extract with ether and dry, evaporate in vacuum) to get the amine. To prepare the diborane in tetrahydrofuran, add 0.3 M NaBH4 (or LiBH4) and 0.4 M BF3 in total 200 ml tetrahydrofuran and keep dry in refrigerator, or generate the diborane in the reaction flask as follows: To a well-stirred suspension of 3.4 g NaBH4 in 150 ml tetrahydrofuran and 0.3M of the styrene or propenylbenzene, add over one hour at room temperature, 15.1 ml BF3 in ether in 20 ml tetrahydrofuran (keep temperature at room temperature); let stand one hour at room temperature and decompose the excess hydride with water; then add the NaOH and chloramine (or hydroxyl-amino-O-sulfonic acid) and proceed as above to get the amine.
Other references on organoboranes:
JACS 82,4710( 1960), 88,5853(1966), Org. Reactions 13,28(1963). Amines from Alkenylbenzenes by Aminoboration BSC 2668 (1973)
Styrenes will give phenethylamines, 1-propenylbenzenes will give amphetamines. The tetrahydrofuran should be dried over KOH pellets and, if desired, distilled from sodium then from lithium aluminum hydride. The diglyme can be vacuum distilled from calcium hydride and stored with calcium hydride. Hydroxylamine-O-sulfonic acid can be purchased or prepared (LAC 702,131 (1967); Inorg. Synth. 5,122(1957)). To a 3-necked flask flushed with a nitrogen stream add 0.096M styrene or 1-propenylbenzene in 200 ml diglyme, and then a solution of 1.52 g (0.04M) NaBH4 in 70 ml diglyme. Keep the temperature at 25ø and add with stirring over 1/2 hour 7.3 g (0.052M) 48% BF3 etherate. Let temperature rise over 3 hours and then reflux 3 hours. Cool and carefully add 11.86 g (0.105M) hydroxylamine-O-sulfonic acid dissolved in 50 ml diglyme. Reflux 3 hours, cool and take up in 10% HCl. Extract with ether, basify the cold acid phase with excess NaOH, extract with chloroform, and dry, evaporate in vacuum to get about 40% yield of the amine.
Amphetamines from Phenylacetates CA 35,5868(1941)
Add 0.44 moles ring substituted phenylacetate, 100 g acetic anhydride and 30 g sodium acetate and heat at 145-150ø for 18 hours to get ca. 0.4 moles of the methyl-phenylacetate (I). Add (I) and formamide (or N-methyl-formamide for the N-methyl cpd.), heat 4-5 hours at 180-195ø, cool and extract with CHCl3. Evaporate in vacuum, dissolve residue in 40% sulfuric acid and heat at 90-125ø for 5-6 hours. Neutralize and add solid NaOH to precipitate about 50% amphetamine. Treat with 10% sulfuric acid to get the sulfate.
Amphetamines from Phenylacetones CA 61,6953(1964)
Exemplified for 2,4,5-trimethoxyamphetamine (I) preparation. Mix 25 g 2,4,5-trimethoxyphenylacetone, 9.3 g hydroxyl-amine-HCl, 15.6 g K-acetate and 400 ml 70% ethanol and reflux 3 1/2 hours. Evaporate in vacuum and extract the residue with 4x150 ml benzene. Wash combined extracts with 2x75 ml water; dry and evaporate in vacuum the benzene (can purify the oil by dissolving in benzene and precipitate by adding petroleum ether) to get out 20 g precipitate (test for activity). Dissolve 18.1 g precipitate in 200 ml methanol and hydrogenate. Acidify to get about 15 g (I).
Amphetamines from Propenylbenzenes J. Prakt. Chem. 137,345, 138,271(1933), JACS 54,273(1932)
Illustrated for 2,4,5-trimethoxyamphetamine (I) preparation. Add a saturated solution of 40 g Na nitrite to 10 g asarone in 90 ml ether. Add dropwise over four hours 75 ml 20% sulfuric acid with stirring. Let stand eight hours; filter and wash precipitate with water, ether, ethanol, and dry. Dissolve 10 g precipitate in 60 ml 8% K carbonate in ethanol with stirring and gentle (below 30ø) heating. Add 150 g ice, acidify with 100 ml dilute HCl and let stand one-half hour at Oø. Filter, wash with water and dry to get about 7 g yellow crystals (recrystallize-methanol) (2-nitropropenylbenzene). Add 4 g crystals to 100 ml ethanol and 50 ml glacial acetic acid; then add 10 ml concentrated HCl or 50 ml concentrated sulfuric acid for the catholyte in a 40 cm2 Hg-cathode in a porous cell surrounded by 3N sulfuric acid anolyte with a water cooled lead anode and reduce at 4 amps (about 0.07 amps/cm2 cathode surface) at 30-40ø for twenty hours or until solution is colorless. Evaporate in vacuum to about 20 ml; cool with ice, basify with NaOH and extract with ether. Wash, dry and dilute the ether (or dry, evaporate in vacuum) to get (I).
Note that this provides an alternative to tetranitromethane for nitration of propenylbenzenes, and an alternative to lithium aluminum hydride or Zn-Hg for reduction of nitropropenes.
Amphetamines from Bromobenzenes JACS 63,602(1941)
0.2 M p-methoxy (or other group)-Br-benzene (see this paper for preparation) and 4.6 g Mg. Rapidly add 18.5 g chloroacetone in 50 ml ether. Evaporate the ether by heating in oil bath and then at about 135ø for one hour. Cool and add ice and dilute HCl; extract the oil with ether and dry, evaporate in vacuum to get about 11 g product (can distill 106/18). 0.057 M of the ketone product in 16 g formamide in 100 ml round bottom flask, with an air condenser. Heat twelve hours at boiling and then reflux with 35 ml 30% NaOH eleven hours and separate the amine layer and dry, evaporate in vacuum to get the amphetamine.
The following papers often employ a glass apparatus called a Soxhlet extractor to get maximum yields in a reduction with lithium aluminum hydride; it is, however, unnecessary.
Phenyisopropylamines and Phenethylamines JMC 13,134(1970)
Mix 5.5 g 3,4,5-trimethoxybenzaldehyde (or analog), 2.5 g NH4 Acetate, 25 ml nitroethane (or equimolar amount nitromethane for the analog), 25 ml benzene and reflux about twenty hours; water being removed with a Dean-Stark tube. Cool and wash with 2x25 ml water, 2x25 ml saturated NaHSO3 and 2x25 ml water and dry and evaporate in vacuum the benzene to get (I). Reduce the nitropropene (or nitrostyrene) by any method such as follows: To a stirred suspension of 3 g lithium aluminum hydride in 50 ml tetrahydrofuran, add 4.4 g (I) in 50 ml tetrahydrofuran and reflux one hour. Cool in ice bath and treat slowly with wet tetrahydrofuran until bubbling stops. Filter and evaporate in vacuum (or filter and extract precipitate with 3X25 ml hot tetrahydrofuran and evaporate in vacuum combined tetrahydrofuran) to get the amine.
For a catalytic reduction of (I) see AP 270,340,410(1932) or proceed as follows (AP 273,481(1935)): Dissolve 0.02 M (I) in 250 ml glacial acetic acid and add 10 ml concentrated sulfuric acid and 1g palladium-carbon (or other catalyst). Reduce at 2 atmospheres H2 and I5o (about fifteen minutes); filter, add 36 ml 5N NaOH and evaporate in vacuum to get the amine. For Zn-Hg reduction of (I) see below. See also JOC 37,1861(1972) for another catalytic reduction of (I).
Substituted Amphetamines From Substituted Benzenes JACS 68,1009(1946)
4M of the substituted benzene and 32.4 g dry FeCl3. Cool to -21ø in an ice-salt bath and add dropwise with stirring over two hours, 76.5 g allyl-Cl and continue stirring three hours. Add about 2 lbs. crushed ice and 100 ml concentrated HCl. Agitate and separate the organic layer and wash with dilute HCl, then water and filter, dry and evaporate in vacuum (or distill 100-115/ 10 with Claisen flask, etc.) to get the substituted-1-phenyl-2-Cl-propane (I). Dissolve 0.16 M (about 27 g) (I) in 450 ml ethanol saturated with NH3 (125 g/L, seal in an iron pipe in autoclave and agitate and heat about nine hours at 160ø. Cool and filter and evaporate in vacuum to get the amphetamine in about 20% yield.
Amphetamines from Benzylmethyl ketones JACS 70,1315 (1948)
10 ml water and 0.2 g Pt oxide (or other catalyst) in 300 ml Parr hydrogenation bottle. Shake in H2 atmosphere ten minutes and add 0.3 M p-methoxy-benzyl-methyl ketone (1-p-methoxy-phenyl-2-propanone) (or analog), 20 g NH4Cl, 225 ml methanol saturated with NH3, 25 ml NH4OH and shake with 1-3 atmospheres H2 until uptake ceases. Filter, wash precipitate with methanol or acidify with HCl and dry, evaporate in vacuum to get p-methoxy-amphetamine or analog.
For the preparation of phenylacetones from nitropropenes see JOC 15,8( 1950). Mescaline J. Chem. U.A.R. 11,401(1968) and many others. Obtain 3,4,5-trimethoxybenzoic acid or synthesize as follows (Org. Synth. Coll. Vol 1,537( 1946)): To a cold solution of 80 g NaOH in 500 ml water in 1 L flask, add 50 g gallic acid; tightly stopper to exclude O and shake occasionally until all acid dissolves. Add 89g (67 ml) dimethyl sulfate, shake twenty minutes, releasing pressure occasionally, and cool to keep temperature below 30ø. Again add 89 g dimethyl sulfate and shake ten minutes. Reflux two hours, add 20 g NaOH in 30 ml water and reflux two hours more. Cool, acidify with HCl; filter and wash with water to get 50 g 3,4,5-trimethoxybenzoic acid (recrystallize-2 L hot water) (can recover more by concentrating the filtrate).
A. Do a Fisher esterification by refluxing 100 g 3,4,5-trimethoxybenzoic acid in ethanol with concentrated sulfuric acid for several hours. Cool, filter, to get the ester (I) (recrystallize-ethanol).
A. (Alternative) 100 g 3,4,5-trimethoxybenzoic acid, 20 g NaOH, 55g NaHCO3 and 300 ml water and add with stirring 94 ml methyl or ethyl sulfate over twenty minutes and reflux one-half hour. Cool, filter, dissolve the precipitate in a small amount hot methanol or ethanol and cool to precipitate (I) (acidify the filtrate to recover unreacted trimethoxybenzoic acid).
B. (Alternative) To 4.6 g lithium aluminum hydride in 200 ml ether, add over one-half hour a solution of 23 g (I) in 300 ml ether. Slowly add 50 ml ice water; decant the ether and add 250 ml ice cold 10% sulfuric acid. Extract with 3x50 ml ether and dry, evaporate in vacuum (can distill 135-137/0.25) to get (II).
C. To a stirred solution of 39.6 g (11) in 150 ml CHCl3 (or CCl4 or benzene), at 0-5ø, add 35 g SO2Cl3 in CHCl over one-half hour; let warm to room temperature and stir for one hour. Evaporate in vacuum and pour residue on ice cold water. Filter and wash precipitate 3X with water to get the trimethoxybenzyl-Cl (III) (recrystallize-benzene-hexane).
C. (Alternative) 25 g (II) and 125 ml ice cold concentrated HCl is shaken vigorously until a homogeneous solution is obtained. Let stand four hours until gummy precipitate forms and dilute with 100 mI ice water. Decant the water and extract with 3x50 ml benzene. Dissolve precipitate in this benzene, wash benzene with water and dry, evaporate in vacuum. Suspend the residue in a small amount ice cold ether, filter throuþh cold funnel and wash with cold ether. Let filtrate stand in refrigerator to get more precipitate of (III) (recrystallize-benzene).
D. 43.2 g (III), 40 g KCN, 300 ml 85% formic acid (or DMSO, acetonitrile, 70% methanol, but lower yield for these). Add 150 ml water and reflux two hours. Cool, filter, and extract filtrate with 3X50 ml CHCl3. Wash CHCl3 with 3x50 ml water and dry, evaporate in vacuum to get the phenylacetonitrile (IV) (recrystallize-benxene-hexane, yield about 34g).
E. HCA 53,50(1970) (see JMC 14,375(1971) or the following for other methods of reducing (IV)). 40 g (IV) in 90 ml methanol and 10 g aqueous 50% Raney-Ni (or substitute catalyst described in chemical hints section). Add dropwise over ten minutes with vigorous stirring a solution of 7.6 g NaBH4 in 25 ml 8N NaOH and cool to keep temperature at 50ø. H2 evolution stops in about five minutes. Filter, wash with methanol and evaporate in vacuum to get mescaline (V).
E. (Alternative) Dissolve 10 g lithium aluminum hydride in 300 ml tetrahydrofuran or ether. Stir and add 20.4 g (IV) in 60 ml tetrahydrofuran or ether over one-half hour. Reflux three hours and cool. Slowly (dropwise at first) add 10 ml concentrated sulfuric acid in 40 ml water; separate the aqueous layer and basify with concentrated NaOH. Filter off any precipitate and extract brown oil with 3x30 ml ether. Wash ether with water, dry and add 1 ml concentrated sulfuric acid and 25 ml ether. Filter and wash the white precipitate with ether to get (V) (recrystallize-ethanol). (Alternatively, add 1.5N sulfuric acid dropwise until bubbling stops, filter (wash precipitate with solvent and add washings to filtrate), and dry, evaporate in vacuum (or bubble HCl gas through, or add a little concentrated HCl and evaporate in vacuum) to get (V)).
Mescaline and Amphetamines via Aldehydes J. Chem. U.A.R. 11,401(1968) and many others.
Illustrated for mescaline
A. To 39.6 g trimethoxybenzyl alcohol (see preceding method for preparation) (or other analog) in 250 ml methanol. stirred and cooled to Oø, carefully add 54 ml Br2 over one hour at Oø. Let temperature rise to room temperature, stir for two hours and add 30 ml saturated Na thiosulfate. Filter off the aldehyde (I) (recrystallize-benzene).
A. (Alternative) To 11 g hexamethylenetetramine in 70 ml CHCl3, add 18 g trimethoxybenzyl-Cl (or other analog) and reflux four hours. Evaporate in vacuum and add 35 ml acetone to cause precipitation. Filter and heat precipitate with 100 ml water for twenty minutes. Add 17.5 ml concentrated HCl and reflux five minutes. Evaporate in vacuum the acetone, cool and filter to get (I).
B. To 40.4 g (I) and 16 g nitromethane (or equimolar amount nitroethane for amphetamines) in 100 ml methanol, add 14 ml 3% methylamine in methanol (under N2 if possible) and let stand at room temperature one day. Cool to -10ø, filter, wash precipitate with cold methanol and dry in vacuum or warm oven to get the nitrostyrene (or nitropropene) (II), which can be reduced as described previously, or as in step C.
B. (Alternative) 40.4 g (I) and 16 g nitromethane (or equimolar amount nitroethane) in 150 ml glacial acetic acid and 15 g NH4 acetate. Reflux 1 1/2 hours; cool, filter, and recrystallize from acetic acid or methanol to get (II).
C. CPB 16,217(1968). Suspend 0.2 M (II) and Zn-Hg from 200 g Zn and 20 g HgCl2 in 2 L ethanol and add with vigorous stirring portions of concentrated HCl until the yellow color disappears. Continue stirring one-half hour, filter, evaporate in vacuum to get about 0.14 M of the amine.
Phenethylamines from Acetophenones JOC 22,331(1957)
Acetophenones can be obtained by various routes such as by reacting acetic anhydride with the substituted benzene (Shirley-PREPARATION OF ORGANIC INTERMEDIATES, 1951, pg. 190) and may then be isomerized, if necessary, with aluminum chloride (JCS 232(1944)).
A mixture of 0.33M of the acetophenone, 39 g of redistilled morpholine and 14.4 g sulfur is refluxed for 12 hours and the warm solution poured into 175 ml hot ethanol. Cool to precipitate about 80% yield of the substituted phenylacetothiomorpholide (I). Mix about 50 g (I), 110 ml acetic acid, 16 ml sulfuric acid and 25 ml water and reflux 5 hours. Decant from the small amount of tar formed with stirring into 850 ml water. Filter, wash the precipitate with water and heat the precipitate with 225 ml 5% aqueous NaOH. Filter and acidify the filtrate with dilute HCl to give about 80% yield of the substituted phenylacetic acid (II). Mix about 21 g (II) and 25 g phosphorus pentachloride (caution), and after the initial reaction subsides, warm on the steam bath 10 minutes. Distill under reduced pressure to remove the POCl and gradually add the residue to ice cold concentrated NH4OH. Filter, wash precipitate with water and air dry (can recrystallize from benzene with a little ethanol added) to get about 18 g (85%) of the substituted phenyl-acetamide (II). (III) may be reduced by various means such as the following. To a stirred suspension of 8.6 g lithium aluminum hydride in 500 ml dry ether add a solution of 10 g (III) in 600 ml boiling reagent benzene, adding additional hot benzene to redissolve any precipitate. Stir and reflux for 22 hours and then hydrolyze by adding water cautiously and 10% sulfuric acid. Filter, heat the precipitate with concentrated HCl to dissolve and cool to preicipitate the substituted phenethylamine.
Phenylethylamines from Benzaldehydes Indian J. Chem. 5,471 (1967), JMC 11,534( 1968)
A. 0.02 M substituted benzaldehyde, 27 g acetic anhydride,12 g fused K acetate in 250 ml round bottom flask with air condenser and CaCl2 tube. Heat on oil bath at 160ø one hour and then at 175ø for four hours. Pour into water (neutralize with Na carbonate and steam distill to recover unreacted aldehyde), cool, acidify and filter to get about 60% yield substituted cinnamic acid (I).
B. Dissolve 10 g (I) in 100 ml water containing 10% NaOH and add with stirring, 300 g 3% Na-Hg portionwise at intervals of one hour and stir for ten hours. Filter, concentrate to one-half volume and acidify to precipitate the hydrocinnamic acid (II) in about 50% yield.
C. 10 g (ll) and 15 g SOCl2 are refluxed on water bath two hours and evaporated in vacuum on water bath. Pour residue into cold liquid NH3 or NH4OH with stirring. Filter, wash precipitate with water to get about 80% yield substituted hydrocinnamamide (III) (recrystallize-benzene or dilute ethanol).
C. (Alternative) To O.1M ethyl-chloroformate in 100 ml CHCl3 at -30ø add a cold solution of 0.1 M (Il) and 0.1 M triethylamine in 100 ml CHCl3 over forty minutes. Stir 1 1/2 hours at -20ø to 5ø and bubble NH3 through the cold mixture for twenty minutes. Stir one-half hour at room temperature, filter and extract the solid with CHCl3. Combine CHCl3 extracts and filtrate and wash two times with cold NaOH solution and two times with water. Dry and evaporate in vacuum to get (III).
D. Pass the chlorine from 3 g KMnO4 and excess HCl into 120 ml 10% NaOH to make a solution of hypochlorite (Clorox may do). Add 10 g finely powdered (III) and stir to dissolve amide, while warming to 50ø. Heat one hour at 85ø, add 30 g KOH and heat two hours. Separate the oil and extract the aqueous layer with ether. Add ether to oil and dry, evaporate in vacuum to get the substituted phenylethylamine (IV).
D. (Alternative) To a stirred and cooled solution of 0.1 M NaOH in 100 ml water at -5ø add 0.04 M bromine over five minutes and stir one-half hour at 0ø. Add 0.02 M (III) and stir 1 1/2 hours at 0-5ø. Stir sixteen hours at room temperature and 70ø for one hour. Cool and extract with ether, dry and evaporate in vacuum to get (IV).
Phenylethylamines from Substituted Benzenes CA 57,6721(1963)
0.1 M m-methoxy-toluene (or analog), 30 ml HCl, 30 ml benzene; cool to 0ø and with cooling and stirring saturate with HCl. Add 0.15 M formaldehyde and then more HCl for fifteen minutes. Stir at room temperature for two hours and dry, evaporate in vacuum the benzene layer to get about 30% 2-methyl-4-methoxy-benzyl-Cl (or analog). 0.5 M (I), 0.8 M NaCN, 5 g NaI or KI in 250 ml dry acetone; stir and boil twenty hours. Filter, wash precipitate with 100 ml acetone and dissolve precipitate with 75 ml benzene. Wash with 100 ml water and dry, evaporate in vacuum to get about 80% yield 2-methyl-4-methoxy-benzyl-CN (II). 0.1 M (II) in 60 ml 10 N NH3 in methanol; 4 g Ni-Cr2O3 and shake in autoclave at 70-100 atmospheres H2 and 120ø to get about 80% yield of the phenethylamine.
Phenylethylamines from Phenols CA 68,86944(1968)
To 5.1 g omega-phthalimidoethyl-Br and 3.1 g 2,6-dimethoxyphenol (or analog) in 500 ml ether add 2.66 g dry AlCl3 portionwise and let stand twenty-four hours at room temperature. Heat two hours at 60ø, filter, wash to recover starting material and dry, evaporate in vacuum to get 25% yield of (I). To an ether solution of diazomethane from 8 g H2N-CON(NO)CH3 add 4 g (I) portionwise and filter, evaporate in vacuum to get about 100% yield of (II). Heat 2 g (II) in 20 ml aqueous HCl for four hours and cool, precipitate, filter, evaporate in vacuum the filtrate to get about 30% yield mescaline.
Phenethylamines JMC 15,214(1972)
This is a rapid, convenient procedure. If trimethoxybenzyl alcohol is used in place of p-anisyl alcohol, mescaline will result. Shake 100 g p-anisyl alcohol (or 0.72 moles analog) with 500 ml concentrated HCl for 2 minutes. Wash the organic phase with water, 5% NaHCO3 and water, and then add over 40 minutes to a stirred slurry of 49 g NaCN in 400 ml dimethylsulfoxide with ice water cooling to keep temperature at 35-40ø. After completing addition, remove cooling bath, stir for 90 minutes and then add to 300 ml water. Separate the small upper layer and extract the aqueous-DMSO layer with 2x100 ml ether. Add the ether extracts to the small upper layer, wash once with water and dry (MgSO4). Add 600 ml ether to a dry flask and chill in ice as 80 g of anhydrous AlCl3, is added portionwise, followed by 23 g of lithium aluminum hydride. Add the washed and dried ether extracts at such a rate as to give gentle reflux without external heat (ca. 1 hour). Stir for 2 hours, ice chill and treat dropwise with 25 ml water then 250 ml 20% aqueous NaOH, with periodic addition of ether through the condenser to replenish losses and facilitate stirring. Filter and wash precipitate with ether; add ether to filtrate and mix with one third its volume of absolute ethanol. Slowly and with continuous swirling and ice cooling add 60 ml concentrated HCl. Cool to 0ø and filter to get the amine hydrochloride in ca. 75% overall yield (or can obtain the crude amine by filtering and drying, evaporating in vacuum the final ether solution). Note the use of concentrated HCl to obtain the crystalline end product in contrast to many other papers which employ HCl gas.
N-Methylation of Amines JMC 13,134(1970), 15,214(1972)
Either phenethylamine or phenylisopropylamine will work. If the hydrochloride salt is available, this should first be changed to the free amine by stirring with concentrated aqueous NaOH.
Treat 0.54 moles of the amine with 100 ml of benzene and 70 g of benzaldehyde in a flask fitted with a Dean-Stark trap and reflux until no more water is present in the condensate (ca. 1 hour) (alternatively, reflux 1/2 hour and then distill until the temperature reaches 100ø): remove the trap and add a solution of 82 g dimethylsulfate in 200 ml benzene through the condenser at a rate sufficient to maintain reflux (ca. 15 minutes). Reflux 30 minutes (or heat 90 minutes on a steam bath), add 200 ml water and reflux (or heat on steam bath) for 1/2 hour more. Separate the aqueous layer, extract it twice with ether or benzene, basify with 50% NaOH and extract twice more. Add the extracts to the organic layer and dry, evaporate in vacuum to get ca. 70% yield of the N-methyl-amine. Can crystallize by dissolving in 500 ml 20% absolute ethanol-ether and treating with 50 ml concentrated HCl while swirling and cooling. The crystals can be further purified by washing with ice cold 20% ethanol-ether and recrystallizing from ethanol.
N-methylation of hallucinogenic amphetamines seems to produce a very smooth, mellow, euphoric trip, and the same is probably true for phenylethylamines. For N-methylation via the imides see JOC 38, I 348(1973). N-methylation appears to decrease the potency. Larger N-alkyl groups seem to have a sedative action.
N,N-Dimethylamines JMC 13,134(1970)
To 14 g formic acid, cooled in an ice water bath, add dropwise 0.016 mole of the amine and then 3.6 g of formaldehyde (ca.10 ml of formalin) and reflux for 5 hours. Cool to room temperature, add 7 ml concentrated HCl and evaporate in vacuum. The resulting oily dimethylamine can be purified by dissolving in 25 ml water, extracting with 2x25 ml CHCl3. Basify the aqueous layer with 2N NaOH and extract with 3x25 ml ether, and proceed as described above for the N-methylamines. This procedure should work for both phenethylamines and phenylisopropylamines, and should affect the trip similarly to N-monomethylation. See the following method for another easy route to N-alkylation which will probably work for dialkylation. Although N,N dialkyl compounds have very little activity, they are probably worth further investigation.
Amphetamines via phenylacetones CT 3,313(1968) CF. JACS 58,1808(1936) and JCS 18(1930)
Note that the following procedure leads from the aldehyde to the amine or N-substituted amine without involving a troublesome catalytic hydrogenation for reducing the intermediate nitropropene. Mix 0.25M substituted benzaldehyde, 0.3M nitroethane, 50 ml dry toluene and 5 ml n-butylamine (or other amine), and reflux 3 hours with a Dean-Stark trap (or prepare the nitro-propene as described elsewhere here). Add 50 g iron powder and 1 g FeCl3 (optional) and reflux while adding 90 ml concentrated HCl over 3 hours. Reflux 1 hour more, add 2 liters of water and extract 3 times with ether, then dry and evaporate in vacuum (or steam distill until about 3.5 liters of distillate is obtained; extract the distillate 3 times with toluene; wash the toluene layers with 7 g NaHSO3 in 225 ml of water, then 3 times with water and dry, evaporate in vacuum) to get the ketone. Mix 0.13M ketone, 28 g formamide (or dimethyl-formamide if the N,N-dimethylamine is desired) and 3 ml formic acid and heat at 160ø. Add 3 more ml formic acid and heat 16 hours at 170-180ø adding formic acid from time to time to keep the pH acid. Distill off the water formed (about 16 ml), cool and extract with 3x70 ml benzene. Distill off the benzene and reflux the residue 7 hours with 30 ml concentrated HCl. Chill, basify with 10% NaOH and extract with 3X70 ml ether. Dry and evaporate the ether in vacuum to get the amine. Since some amines are unstable to heating, it is perhaps best just to dry and evaporate the benzene extract.
To obtain an N-substituted amine reflux 0.1 M ketone, 17 g aluminum filings or foil, 50 ml ethanol, 40 ml 30% aqueous n-butylamine (or other amine), and 0.5 g of mercuric chloride for 3 hours. Cool and pour on 500 g crushed ice and 200 ml 10% KOH. Extract 3 times with ether and dry, evaporate in vacuum (or wash combined ether layers 2 times with 1O% HCl, basify acid extract with 15% NaOH and extract 3 times with ether and dry, evaporate in vacuum) to get the n-butyl-amine (or other amine).
Alkoxybenzaldehydes 2,4,6-Trimethoxybenzaldehyde JCS 4964(1952)
This method should also work for 3,4,5-trimethoxybenzene and other symmetrically substituted benzenes. To 42 g 1,3,5-trimethoxybenzene, 30 g formanilide and 200 ml ether add 19 g POCl3 and let stand twelve hours. Evaporate in vacuum, add 900 ml 5% NaOH and steam distill residue to get the aldehyde (recrystallized benzene-ligroin). For a different synthesis see Org. Synth. 2,11 (1940).
Substituting methyl sulfate for methylene sulfate will probably give the dimethoxybenzaldehydes. Dissolve 4 g 3,4-dihydroxybenzaldehyde (or any other benzaldehyde having adjacent OH groups) and 7.6 g KOH in 50 ml water. Heat to 50ø (under N2 if possible) with stirring and add 5 g methylene sulfate; stir and heat two hours. Add 500 ml water and sufficient K sulfate to dissolve the precipitate. Extract with ether, acidify the aqueous phase with HCl to precipitate unreacted aldehyde, and dry, evaporate in vacuum the ether to get the title compounds (recrystallize-methanol).
2,4,5-Trimethoxybenzaldehyde JACS 57,1126,2739(1935)
To 13 g 3,4-dimethoxyphenol in 20 ml methanol add a solution of 5.3 g KOH in 100 ml methanol and then 12 g methyl iodide. Reflux two hours, add 300 ml water and make pH 10 with 5% NaOH. Extract with ether and dry, evaporate in vacuum the pooled extracts to get a clear oil. Mix 17.3 g N-methyl-formanilide and 19.6 g POCl3 and let stand at room temperature for one-half hour. Add 8.5 g of the oil, heat two hours on steam bath (or boiling water) and pour black viscous product on 800 g cracked ice and let stand three hours, or until no more precipitation to get title compound. Filter (recrystallize-methanol).
Simple methods of preparing phenylacetonitrile from diazoacetonitrile and triphenylboron are given in JACS 90,6891 (1968) and from the borophenyl-9-borabicyclo (3.3.1) nonane (BBN) and Cl-acetonitrile in JACS 91,6854(1969). These methods should work with substituted phenyl compounds to give mescaline and analogs. Likewise (JACS 90,5936(1968)), a preparation of phenylketones from triphenylboron or BBN and diazoacetone, or bromo-acetone (JACS 91,6852( 1969)) may be used to prepare the phenylacetones which can be reduced to the amphetamines in one step as already described. For synthesis of BBN see JACS 91,4304(1969) and for borabicyclononane see JACS 90,5280(1968). The amphetamine and mescaline analogs which can be obtained by replacing carbon atoms with O, N, or S atoms may also be active, but little work has been done on this. For the synthesis of thienyl analogs see JACS 64,477(1942).
N-Methyl Mescaline HCA 35,1577(1952) p-Methylephedrine Pharmazie 24,735(1969) 4-Nitropropenylbenzene CCI 100,846(1970) Amphetamines and Phenylethylamines JMC 11,186(1968), 13, 26,134(1970); JOC 19,11 (1954), 20,102,1292(1955), 22,331 (1957), 23,1979,2034(1958), 25,2066(1960); Alab. J. Med. Sci. 1,417(1964); JCS 18(1930); BSC 835(1962); BER 63,3029 (1930), 65,424(1932), 67,696(1934); CA 6953(1964); Arznei. Forsch. 9,157(1959); JACS 51,2262( 1929), 63,602(1941), 76,5555(1954); Pharmazie 22,19(1967); CT 3,313(1968). Bromoamphetamines JMC 15,413(1972) N-substituted mescaline derivatives and methamphetamine analogs Diss. Abst. Int. 32B,5704,5706(1972). Methambhetamine analogs JMC 16,14(1973), MMDA CJC 46,75 (1968). See CT 8,308(1973) for a route from phenethyl or phenylpropylchlorides to the amines. For older MDA syntheses see JACS 62,425(1940); JCS 15(1943), 1527(1951). For other compounds related to STP see CJC 51,1402(1973), and Psychopharmacology Communications 1,93(1973) MDA Japanese Patent 8573 (5 Oct 1956)