Thank you Azole and GC!
Well, speaking about [1], we now have the yield in the bromination step: 75% and the yield in the swap step is improved (altough the method in the other article is inspired by this one), good!
Ok, lets see what the yields are from the alpha-chloro analogs with the other Arch Pham ref
(Archiv der Pharmazie (Weinheim, Germany) (1978), 311(3), 248-55) (
EDIT: Retrieved (Thanks again GC! ) : ref [4]) and if the chem abstract is correct on it, and with Lego's help [2] we will an easy synth of DMT from indole, chloroacetylchloride (cheap as dirt), SnCl4, dimethylamine
Post 448644
(Chimimanie: "Dimethylamine from formaline", Tryptamine Chemistry) and NaBH4.
At least we have a good synth already from indole, acetonitrile (cheap as dirt
), SnCl4, Yo ol' Bromine, aq dimethylamine and NaBH4. (
EDIT: See proposed experimental)
Nice Good that LiAlH4 is not needed and can bee replaced by borohydride!
Good work, bees.
EDIT:Thanks to GC-MS [4] we have now the yield for the Cl swap: 74%.
And now, let me...
...propose an
Experimental: So here is an example of a 3 steps synthesis of DET taken from the linked posts above:indole + chloracetyl chloride + SnCl4 => 3-chloroacetyl-indole: [2]
To a stirring solution of indole (1.17 g, 10 mmol) in CH2Cl2 (20 mL) under argon at 0 °C was added SnCl4 (1.44 mL, 12 mmol) in a single portion via syringe. After the ice bath was removed, the mixture was stirred at room temperature for 30 min, and then chloro acetylchloride (10 mmol) was added in small portions to the suspension, followed by nitromethane (15 mL). The mixture was stirred for 8 h at room temperature. After being quenched with ice and water (30 mL), the mixture was filtered to remove inorganic precipitates, and the organic material was extracted with ethyl acetate (50 mL). The organic phase was dried over Na2SO4 and concentrated at reduced pressure to give the product as a crystalline solid.
Yield: 80%, mp: 235°C. [4]
3-chloroacetyl-indole => 3-(N,N-diethylaminoacetyl)-indole: [4]
7.7 g (0.04 mol) 3-chloroacetyl-indole was suspended in 300 mL abs toluene and refluxed for 2 hours with 8.8 g (0.12 mol) diethylamine. The solvent is evaporated, the reaction mixture cooled down and the precipitate collected and washed with water. The residual base was recrystallized from toluene. Formation of the HCl salt was achieved by means of gaseous HCl in methanol.
Yield: 74%, mp: 205-215°C.
3-(N,N-diethylaminoacetyl)-indole (keto-DET) => DET: [1]
The 3-(N,N-diethylaminoacetyl)-indole was refluxed with twice its weight of sodium borohydride in 1-propanol for 15 hours. The solvent was evaporated in vacuo and the residue was partitioned between water and chloroform. The chloroform extract was extracted with 3N-hydrochloric acid to separate the tryptamine from accompanying 3-unsubstituted indole. The acid extracts were alkalized with 10% sodium hydroxide and the liberated bases extracted into chloroform. The tryptamine was isolated either as the free base or picrate salt.
Yield: probably between 40-50% (49% for DMT but it seem the diethyl is a bit lower in yield), mp: 84-87 °C (freebase, Tihkal).
Alternatively, synthesis of DMT in 4 steps:indole + SnCl4 and acetonitrile => 3-acetyl-indole: [2]
To a stirring solution of indole (1.17 g, 10 mmol) in CH2Cl2 (20 mL) under argon at 0 °C was added SnCl4 (1.44 mL, 12 mmol) was added in a single portion via syringe. After the ice bath was removed, the mixture was stirred at room temperature for 30 min, and then acetonitrile (100 mmol, 5.3 mL) was added in small portions to the suspension, followed by nitromethane (15 mL). The mixture was stirred for 4 h at room temperature. After being quenched with ice and water (30 mL), the mixture was filtered to remove inorganic precipitates, and the organic material was extracted with ethyl acetate (50 mL). The organic phase was dried over Na2SO4 and concentrated at reduced pressure to give the product as a crystalline solid.
Yield: 96%, mp: 185-191°C.
3-acetyl-indole => Indolyl-3-bromomethylketone: [3]
15.9 g (0.1 mol) indolyl-methylketone was suspended in 50 mL methanol. Under stirring and cooling, 16 g (0.1 mol) bromine was added dropwise; doing so, the ketone dissolved completely. When the addition was complete, the reaction mixture was refluxed for 1-2 hours on the waterbad. The precipitation of brick-red crystals from the dark red solution was noted; the crystals were removed via suction filtration, washed with ether and recrystallized from methanol. The mp and mixed mp with authentic sample was 230°.
Yield: 17.8 g = 74.8%, mp: 230°C.
Indolyl-3-bromomethylketone => Indolyl-3-dimethylaminomethylketone (keto-DMT) [3]
11.9 g (0.05 mole) indolyl-bromomethylketone was dissolved in 60 mL hot IPA and refluxed on the waterbath for 1 hour after addition of 17.8 g (0.15 mol) 38% aqueous dimethylamine solution. When the reaction was halted, the volume was reduced to about half and colourless crystals started to form. They were isolated via suction filtration and recrystallized from ethanol.
Yield: 8.5 g = 84.2%, mp: 208-209°C; mp HCl salt: 229°C; mp picrate salt: 181-183°C.
Indolyl-3-dimethylaminomethylketone (keto-DMT) => DMT-with sodium borohydride: [1]
The 3-(N,N-dimethylaminoacetyl)-indole was refluxed with twice its weight of sodium borohydride in 1-propanol for 15 hours. The solvent was evaporated in vacuo and the residue was partitioned between water and chloroform. The chloroform extract was extracted with 3N-hydrochloric acid to separate the tryptamine from accompanying 3-unsubstituted indole. The acid extracts were alkalized with 10% sodium hydroxide and the liberated bases extracted into chloroform. The tryptamine was isolated either as the free base or picrate salt.
Yield: 49%, mp: 42-43°C.
-with lithium aluminium hydride: [3]
A suspension of 2.3 g (0.06 mol) LAH in 50 mL THF was added to a solution of 4.0 g (0.02 mol) indolyl-dimethylaminomethylketone in 30 mL THF. The mixture was stirred for 30 minutes at room temperature, followed by 2 hours on a boiling waterbath. The THF was removed via distillation and water added to the complex. By doing so, a smudgy mixture of base and aluminium hydroxide was obtained. It was extracted with acetone after decanting the water; when the acetone was dried over potassium carbonate, it was evaporated, hereby giving a brownish oil. The oil crystallized after purification with ether-petroleum ether. Recrystallization from ethyl acetate-petroleum ether gave the compound.
Yield: 2.8 g = 73.7%, mp: 48-49°C; mp of the picrate salt: 170°C.
Summary (total yields presumed) from indole:-3 steps w/ chloro acetyl chloride: DET: 80% x 74% x ? (40%) = 24%
DMT: 80% x ? (75%) x 49% = 29%
-4 steps w/ acetonitrile:DMT (NaBH4): 96% x 75% x 84% x 49% = 30%
DMT (LAH): 96% x 75% x 84% x 74% = 45%
(Unrelated:) Shulgin yield from indole with oxalyl chloride / LiAlH4 route:
DMT: 79% x 91% = 57%
Well, those are viable alternative routes, considering everybee that is interested in 2C-B has already acetonitrile, nitromethane, bromine and NaBH4, the second route look good, as aquisition is only indole + SnCl4
, otherwise just buy chloroacetylchloride (or bromo BTW, yield is 4% better) and skip the halogenation step.
Well, it is nice to see some cooperation on certain subjects
. We shall cooperate more often
.
References (linked posts):[1]:
Post 448729
(Chimimanie: "DMT from 3-acetyl indole + 5-cyano/nitro DMT", Tryptamine Chemistry)[2]:
Post 448820 (missing)
(Lego: "An improved method to obtain 3-acylindoles", Tryptamine Chemistry)[3]:
Post 451451
(GC_MS: "Reduction of indolyl-3-aminomethylketones", Tryptamine Chemistry), above post.
[4]:
Post 451584 (missing)
(GC_MS: "Synthesis of 1-, 2- and 3-(aminoacetyl)indoles", Tryptamine Chemistry)