2-M · 6-(2-Aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran ·
SYNTHESIS: To a solution of 43.2 g KOH pellets in 250 boiling EtOH there was added 96 g 4-methoxyphenol followed by the slow addition of 131.2 g allyl bromide, and the mixture was held under refluxing conditions for 16 h. After cooling, the reaction was added to 1.6 L H2O, and made strongly basic with 25% NaOH. This was extracted with 3×100 mL CH2Cl2, the extracts pooled, washed once with dilute NaOH and then once with dilute HCl. Removal of the solvent under vacuum gave 93.8 g of 4-allyloxyanisole as a pale amber oil, which was used in the following reaction without further purification.
A round-bottomed flask containing 93 g crude 4-allyloxyanisole was equipped with an immersed thermometer and heated with an external flame until an exothermic reaction set in at 230 °C. The temperature rose to 270 °C and it was maintained there with the flame for five minutes. After cooling to room temperature, the reaction mix was poured into 2 L H2O and made strongly basic with the addition of 25% NaOH. This dark aqueous phase was washed with 2×200 mL CH2Cl2, and then acidified with HCl. This was then extracted with 2×200 mL CH2Cl2, and the pooled extracts washed first with saturated NaHCO3 and then with H2O. Removal of the solvent under vacuum gave 65.6 g of 2-allyl-4-methoxyphenol as a clear, amber oil. To a solution of 1.66 g of this crude phenol in 5 mL hexane with just enough CH2Cl2 added to effect a clear solution, there was added 1.3 g phenyl isocyanate followed with three drops of triethylamine. An exothermic reaction ensued which spontaneously deposited white crystals. These was removed and hexane washed to give 2-allyl-4-methoxyphenyl N-phenyl carbamate, with a mp of 88–89 °C. The acetate ester, from the phenol and acetic anhydride in pyridine, did not crystallize.
To a solution of 37.7 g 2-allyl-4-methoxyphenol in 125 mL glacial acetic acid there was added 19 g zinc chloride followed with 63 mL concentrated HCl. The mixture was held at reflux temperature for 40 min, then cooled to room temperature, diluted with 300 mL H2O, and extracted with 2×200 mL CH2Cl2. The pooled extracts were washed repeatedly with 8% NaOH until the washings remained basic. Removal of the solvent under vacuum gave a clear pale yellow oil that was distilled at the water pump. A fraction boiling at 150–165 °C was 5-methoxy-2-methyl-2,3-dihydrobenzofuran which weighed 25 g and which was a highly refractive colorless oil. The infra-red spectrum indicated that some small amount of hydroxy group was present, but the NMR spectrum was in complete accord with the benzofuran structure. A higher cut in this distillation gave 4.5 g of a phenolic product tentatively assigned the structure of 4-methoxy-2-propenylphenol. The target dihydrobenzofuran has also been synthesized from the open-ring o-allyl phenol in acetic acid solution with the addition of a catalytic amount of concentrated H2SO4.
To a half-hour pre-incubated mixture of 69 g POCl3 and 60 g N-methylformanilide there was added 29.0 g 5-methoxy-2-methyl-2,3-dihydrobenzofuran and the mixture was heated on the steam bath for 2 h. The reaction mixture was poured into 1 L H2O, and allowed to stir overnight. The brown gummy solids were removed by filtration, and air dried as completely as possible. These weighed 32 g and were shown by GC on OV-17 to consist of two benzaldehyde isomers in a ratio of 7:2. This was triturated under 18 mL MeOH, and the undissolved solids removed by filtration and washed with 6 mL additional MeOH. The mother liquor and washings were saved. The 17.8 g of dull yellow solids that were obtained were repeatedly extracted with 75 mL portions of boiling hexane (4 extracts were required) and each extract, on cooling, deposited yellow crystals of the major aldehyde. The dried crystals of 6-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran were combined (9.5 g) and had a mp of 80–82 °C. The methanol washes saved from above were stripped of solvent, and the sticky, orange solids that remained were enriched in the minor aldehyde isomer (3:2 ratio). Several injections of this crude material into a preparative GC OV-17 column gave sufficient quantities of the “wrong” isomer for NMR characterization. The 2-methyl group was intact (eliminating the possibility of a dihydrobenzopyran isomer) and the ring meta-proton splitting required that the formyl group be in the benzofuran 7-position. This crystalline solid was, therefore, 7-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran.
A solution of 9 g of 6-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran in 35 mL glacial acetic acid was treated with 6 mL of nitroethane followed with 3.1 g anhydrous ammonium acetate. This mixture was heated on the steam bath for 4 h, diluted with half its volume with warm H2O, and seeded with a bit of product that had been obtained separately. The slightly turbid solution slowly crystallized as it cooled, and was finally held at 0 °C for several h. The deep orange product was removed by filtration, washed with 50% acetic acid, and air dried to constant weight. There was thus obtained 7.0 g 5-methoxy-2-methyl-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran with a mp of 89–90 °C from MeOH.
A suspension of 5.0 g LAH in 500 mL of well stirred anhydrous Et2O at a gentle reflux, was treated with a warm, saturated solution of 7.0 g 5-methoxy-2-methyl-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran in Et2O added dropwise. The mixture was kept at reflux temperature for 36 h, allowed to stand 2 days, and then the excess hydride destroyed by the cautious addition of 500 mL 6% H2SO4. The phases were separated, and the aqueous phase washed with 2×200 mL CH2Cl2. A total of 125 g potassium sodium tartrate was added to the aqueous phase, and sufficient 25% NaOH added to bring the pH to about 10. This phase was extracted with 3×150 mL CH2Cl2, and the pooled extracts were stripped of solvent under vacuum. The residual oil (4.8 g, amber in color) was dissolved in 300 mL anhydrous Et2O which, upon saturation with anhydrous HCl gas gave a clear solution that suddenly deposited white crystals. The hydrochloride salt of 6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran weighed 2.3 g and was not satisfactory as a solid derivative, but it appears that the oxalate salt is both nonhygroscopic and quite stable. It (F-2) had a mp of 216–218 °C and it displayed a textbook NMR.
DOSAGE: greater than 15 mg.
EXTENSIONS AND COMMENTARY: This material, which is certainly a mixture of two diastereoisomeric pairs of racemates since there are two chiral centers present, showed no effects at levels of up to 15 milligrams orally. Doses of 100 mg/kg were without effects in mice following i.p. injections, although half again this amount proved to be lethal. In rats trained to discriminate
This was the prototype compound that was originally put together to justify giving a paper at a marijuana conference in Sweden, in 1968. Although I had never done much with marijuana or with its principal ingredients, I thought maybe I could bend the topic a bit to embrace some potentially active phenethylamines. There is a story of an international conference held in Geneva a few years earlier to discuss the worrisome decrease in the elephant population. A German zoologist invested a full eight-hour day in a summary of his 21 volume treatise on the anatomy and the physiology of the elephant. A French sociologist presented a lively slide show on the mating rituals and rutting behavior of the elephant. And a rabbi from Tel Aviv entitled his talk: “Elephants and the Jewish Problem.” My Swedish talk should have been named “Marijuana and the Psychedelic Amphetamines.” The memorable story of meeting the chief of the Swedish equivalent of the Bureau of Narcotics, and ending up playing Mozart sonatas in the attic of his home, has been spun out elsewhere in the book.
The original concept was a grand plan to imitate two of the three rings of tetrahydrocannabinol. There is an aromatic ring (with an alkyl group and two oxygens on it) and it is fused to a pyran ring with a couple of methyl groups on it. So, if one were to tie the methyl group at the 4-position of
The isolation of characterizable quantities of 7-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran from the benzaldehyde recipe above gave a fleeting fantasy of a whole new direction that this little project might go. If this unexpected benzaldehyde were to be converted to the corresponding amphetamine, one would have
The plain furan analogue, without any methyl groups on it, has been made. Five-methoxybenzofuran formed the 6-formyl derivative (the aldehyde) with a mp of 79–80 °C and from it the nitrostyrene (orange needles, mp 89–91 °C) and the final amphetamine (white solids, as the methane sulfonate, mp 141–144 °C) were prepared in a manner similar to the preparation of F-2 above. In the rat studies, it was three times more potent than F-2, but still some 15 times less potent than
13 May 2016 · · Isomer Design
About PiHKAL · info
This version of Book II of PiHKAL is based on the Erowid online version, originally transcribed by Simson Garfinkle and converted into HTML by Lamont Granquist. I drew also on “Tyrone Slothrop’s” (Unfinished) Review of PIHKAL to enumerate the many analogues mentioned in PiHKAL but not described at length. Many, many others have since been added.
I have tried here to expunge any artifacts introduced by the earlier transcriptions and restore the typographic niceties found in the printed edition. I’ve also made minor changes to some chemical names in line with current nomenclature practice. Typically the change is little more than expanding a prefix or setting it in italics. The history page has further details.
“At the present time, restrictive laws are in force in the United States and it is very difficult for researchers to abide by the regulations which govern efforts to obtain legal approval to do work with these compounds in human beings.“No one who is lacking legal authorization should attempt the synthesis of any of the compounds described in these files, with the intent to give them to man. To do so is to risk legal action which might lead to the tragic ruination of a life. It should also be noted that any person anywhere who experiments on himself, or on another human being, with any of the drugs described herein, without being familiar with that drug’s action and aware of the physical and/or mental disturbance or harm it might cause, is acting irresponsibly and immorally, whether or not he is doing so within the bounds of the law.”
The copyright for Book I of PiHKAL has been reserved in all forms and it may not be distributed. Book II of PiHKAL may be distributed for non-commercial reproduction provided that the introductory information, copyright notice, cautionary notice and ordering information remain attached.
PiHKAL is the extraordinary record of the authors’ years exploring the chemistry and transformational power of phenethylamines. This book belongs in the library of anyone seeking a rational, enlightened and candid perspective on psychedelic drugs.
Though Sasha and Ann have put Book II of PiHKAL in the public domain, available to anyone, I strongly encourage you to buy a copy. We owe them — and there’s still nothing quite like holding a real book in your hands.
PiHKAL (ISBN 0-9630096-0-5) is available for US$24.50 (plus $10 domestic first-class shipping) from Transform Press.Transform Press,
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