See
Post 443756 (missing)
(azole: "DET + alpha-ET synth&reports, Part II, exptl.", Russian HyperLab) for the source version. Some corrections have been made, and the procedure for alpha-ET synthesis has been rewritten in accordance with the notes found by SWIM recently (when posting the initial (Russian) version, he supposed that there were none left).
Experimental part. Diethylamine was dried over NaOH pellets overnight and used without distillation. Chloroform, stabilized with unknown (within 0.1-0.5%) amount of EtOH was used without purification. Indole-3-acetic acid (beige scatole-smelling crystals) was used without purification, too. Commercial 95% ethanol is designated as EtOH for short. Tetrahydrofuran was distilled from sodium benzophenone ketyl solution under argon. Diethyl ether was peroxide-free (negative NaI test). Solutions were dried by filtering through a pad of Na
2SO
4-Celite mixture and evaporated on a rotary evaporator (aspirator vacuum, 40°C water bath). To minimize losses in the course of extraction or filtration, the traces of a substance were extracted from an aqueous phase or washed from a filter with an additional volume of a solvent. Room temperature (19-22°C) is referred to as rt.
Indole-3-acetic acid and its potassium salt (hydrolysis of ethyl indole-3-acetate). IndCH
2CO
2Et (10.0 g) was suspended in EtOH (40 mL); pelleted KOH (1.2 eq.) was added, and the mixture was stirred at 40°C for ~2 h (this may appear longer than necessary; the reaction is finished when a drop of the mixture gives a clear solution in water). Immediately after the addition of KOH, oil separated (the starting ester was salted out); after several minutes potassium indole-3-acetate began to precipitate as beautiful white leaflets, while KOH and the ester dissolved. After completion of hydrolysis, the reaction mixture was allowed to stand in a refrigerator for an hour; the potassium salt of IAA was filtered off with suction, washed with cold EtOH and air-dried. Yield 7 g.
The mother liquor was evaporated, dissolved in water (20 mL), treated with activated charcoal, filtered and acidified with AcOH with stirring. Indole-3-acetic acid, precipitated as beige crystals, was filtered off and dried
in vacuo. Yield 2.4 g.
N,N-Diethylindole-3-acetamide picrate. Indole-3-acetic acid (2.4 g, 14 mmole) was suspended in CHCl
3 (50 ml) in a RBF fitted with a reflux condenser and a magnetic stirbar, and Et
2NH (12.8 mL, 124 mmole) was added. The solution formed was heated to ~50°C , and POCl
3 (2.6 mL, 28 mmole) was added dropwise with stirring at a rate slow enough to avoid vigorous boiling. The mixture was refluxed for 5 min. and cooled to rt with tap water. It was acidic to universal indicator paper. Diethylamine was added to make the pH alkaline (it may well be unnecessary), and the mixture was refluxed for 5 minutes again. Then it was cooled; water (50 mL) was added; the organic layer was separated, washed with 10% Na
2CO
3 solution, then with water, 5% AcOH, with water again, dried and evaporated. The resulting mixture of diethylamides of indole-3-acetic and phosphoric acids (viscous brown syrup) was dissolved in EtOH (10mL) and a warm solution of picric acid (3.77 g, 16.5 mmole) in EtOH (~20-25 mL) was added to it. After cooling to rt, water was added dropwise with stirring until the solution became slightly cloudy. Several drops of EtOH were added to make it clear again, and crystallization was stimulated. After keeping the mixture for some time in a refrigerator, the product (fine light-yellow crystals) was filtered off with suction, washed with cold (-20°C) EtOH, and dried. Yield >80%.
Note: possibly, the solution of the picrate before crystallization was treated with activated charcoal when still warm, and filtered. SWIM couldn’t remember the actual procedure of crystallization.
Indole-3-acetic acid diethylamide. The picrate obtained in the previous step was suspended in DCM (50 mL); 5% aq. NH
3 (excess) was added, and the mixture was shaken for 5 minutes. The crystals of the picrate dissolved, and ammonium picrate precipitated. The mixture was filtered; the organic layer was separated, dried and evaporated. The amide was obtained in nearly quantitative yield as a slightly yellow odorless syrup.
N,N-Diethyltryptamine fumarate. A 100 mL RBF fitted with a reflux condenser, magnetic stirbar, dropping funnel and Ar inlet was dried in the vacuum of an oil pump for 10 minutes, then filled with dry Ar. Absolute THF (30 mL) was added, followed by LAH (2.5 g), and the resulting suspension was refluxed for 0.5 h to dissolve as much LAH as possible. After cooling to rt, a solution of the amide obtained in the previous step in abs. THF (20 mL) was added dropwise with stirring at a rate that kept the reaction controllable, and the mixture was refluxed for 2 h, cooled with ice-water, and IPA was added dropwise with good stirring until gas evolution ceased (at some moment, stirring was difficult due to gel formation, but soon the mixture became less viscous). The precipitated hydroxides were made white and granular by addition of 15% aq. NaOH with stirring, filtered off with suction, and washed with IPA several times. The filtrate and washings were evaporated; the residue was dissolved in ice-cold dilute H
2SO
4 (couldn't remember the concentration, perhaps 1:50 v/v), and washed with DCM to remove neutral impurities. The aqueous phase was made basic with a cold NaOH solution, and extracted 3 times with DCM. The extracts were dried and evaporated. The residue (clear brownish syrup) crystallized on standing in a refrigerator. The yield was high.
Diethyltryptamine base was dissolved in MeOH; a warm methanolic solution of fumaric acid (0.55 mole per mole of the amine) was added, and the mixture was evaporated to form a foam. This was redissolved in MeOH (1 mL/g); EtOAc (~2 mL/g) was added (the solution should be still clear), and crystallization was stimulated. An additional amount of the product was precipitated with Et
2O . Yield 2.2 g (58% from IAA) of nearly white crystals. The substance must be protected from light (when kept in a glass vial, it became brown, and the color was deeper on the more exposed side).
Alpha-ethyltryptamine (fumarate and acetate). The mixture of (EtCO)
2O (30 mL) and potassium indole-3-acetate (7 g) was stirred at 140-148°C for 12 h (4+8 in two consecutive days) in a RBF with a reflux condenser connected to a bubble-counter to prevent excessive contact with the atmospheric oxygen. At 100-110° a clear solution formed. Gas evolution had stopped after ~11 h heating. TLC (97:3 CHCl
3 – Me
2CO v/v, Ehrlich’s reagent) showed the presence of at least 4 indolic compounds. To the cooled mixture MeOH (20 mL) was added to destroy excess anhydride, and the mixture was allowed to stand for 0.5 h. Then it was diluted with CHCl
3 (100 mL) and washed with water, then with aq. Na
2CO
3 to remove acids, dried and evaporated. Toluene was distilled off the residue to remove traces of water and CHCl
3. The resulting dark brown semisolid was dissolved in MeOH (40 mL) and PhMe (10 mL) (without PhMe the dissolution was incomplete), and 1N MeONa in MeOH (5 mL) was added. The mixture remained strongly alkaline during the reaction. After 1.5 h at rt it was made neutral with AcOH. The solution, which supposedly contained 1-(indol-3-yl)-2-butanone, was used directly in the next step.
Aluminum powder (7 g, particle size perhaps 0.2-0.5 mm) was amalgamated using HgBr
2 (~200 mg) solution, washed with water, suspended in IPA (80 mL) and 25% aq. NH
3 (10 mL), and this was added to the solution of indolylbutanone. There was slow evolution of hydrogen. To accelerate the reaction, a solution of NaOH (~0.6 g) in water (2 mL) was added with stirring. As the mixture was stirred, the temperature rose to ~45°, and the rate of hydrogen evolution reached ~75 mL/min. Three 2 mL portions of aq. ammonia were added within the next 2 hours, and the mixture was stirred overnight (at some moment stirring stopped because of Al(OH)
3 gel; however, all aluminum had reacted). Large excess of aq. NaOH was then added, and the mixture was extracted several times with PhMe. The amine was then extracted from PhMe into cold dilute H
2SO
4. Some dark insoluble tar formed upon acidification, and the aqueous extract darkened in several minutes. Dark-colored impurities were partly removed by extraction with chloroform; the mixture was then made strongly alkaline with cold NaOH solution, and was extracted 2 times with DCM. The extracts were dried and evaporated to leave a clear brownish syrup (0.42 g) which crystallized after ~0.5 h standing in a refrigerator. The odor was strong but not indolic at all; rather, it was like some sort of grape wine known for its fragrance, Isabella.
The crystals were dissolved in MeOH, and a warm (~40°C) solution of fumaric acid in minimum amount of MeOH was added to adjust the pH to 7. Acetonitrile and EtOAc were then added until the solution became slightly cloudy. Crystallization was stimulated, and the solution with crystals was kept for ~1 h in a refrigerator. The crystals were filtered off, washed with 1:1 MeCN-EtOAc, and dried. Yield 211 mg of AET fumarate (?). (The procedure for the fumarate formation and crystallization may be presented inaccurately.)
The mother liquor (very dark by that time) was concentrated and the residue was partitioned between DCM and cold dilute H
2SO
4 (some dark tar formed again). The aqueous phase was separated, made basic with a cold NaOH solution, and extracted twice with DCM. The extracts were dried and evaporated to afford a syrup (0.18 g) which was treated with AcOH (0.07 mL) in MeOH (2 mL), evaporated to dryness, and redissolved in EtOAc (2 mL), containing AcOH (0.03 mL). Crystallization was stimulated, and the solution with crystals was kept for a while in a refrigerator. The crystals were filtered off, washed with cold EtOAc, and dried to yield 85 mg of AET acetate (?). The overall yield is ~4%.
