Synthesis of 4-(alkylthio)-2,5-dimethoxyphenethylamine derivativesThis is a repost of
Post 210276 (missing)
(Sonson: "Re: New route to PEAs?", Novel Discourse) with a little more experimental detail but since Rhodium asked it in the Wanted References sticky thread and since I had already OCRed it month ago I repost it.
They synthetise these phenethylamines to do THC analogs from the skeleton of 2-CT-# analogs. It always shock me when I see the similarities between the structure of different entheogens: lysergides, tryptamines, benzofuranamines, phenethylamines, THC.
Well enough rambling, now place to the fun part:
Experimental:1,4-dimethoxy-2-(pentylthio) benzene (IVa)A solution of sodium ethoxide (from 9.75g Na and 200 ml ethanol) was treated with 63.6g 2,5-dimethoxythiophenol and 67.4g pentyl bromide and the mixture was stirred and refluxed for 5h. Ethanol was distilled off, the residue was diluted with 250ml water and the mixture was extracted with benzene. The dried extract was processed by distillation; 86.8g (97%) bp 139-142°C/0.1 kPa, mp 38-39°C (MeOH)
2-(Heptylthio)-1,4-dimethoxybenzene (IVb)Similar reaction of sodium ethoxide (from 6.30g Na and 130 ml ethanol) with 46.7g 2,5-dimethoxythiophenol and 50.3g heptyl bromide gave 73.5g (theoretical) of homogeneous IVb melting at 46-47°C. The melting point remained unchanged after crystallisation from methanol.
2-(Chloromethyl)-1,4-dimethoxy-5-(pentylthio)benzene(Va)see
Post 210276 (missing)
(Sonson: "Re: New route to PEAs?", Novel Discourse)2-(Chloromethyl)-5-(heptylthio)-1,4-dimethoxy-benzene(Vb) A mixture of 20 ml 38% aqueous formaldehyde, 10 ml HCl and 40 ml dioxane was saturated for 10 min with HCl and the mixture was similarly reacted (cfr Sonson's post) with 26.8g IVb in 20 ml dioxane and similarly processed. Crystallization of the inhomogeneous residue (31.3g) from 100 ml acetone gave 26.7g of the diphenyl compound. Processing of the mother liquor gave 19.05g (60%) of Vb mp 66-69°C (light petroleum)
4-(pentylthio)-2,5-dimethoxyphenyl)acetonitrile(Vb)see Sonson's post
4-(heptylthio)-2,5-dimethoxyphenyl)acetonitrile(Vb)A similar reaction (see Sonson's post) of 25.3g Vb with 12.65 NaCN in 80ml DMF gave 26g of an inhomogeneous solid which was crystallised first from 50ml MeOH and then from 50ml cyclohexane affording 17.3g (71%) of VIb, mp 69-71°C (light petroleum)
2-(2,5-dimethoxy-4-(pentylthio)phenyl)ethylamine(XIIIa)A solution of 15.7g AlCl3 in 110 ml ether was slowly added to a stirred solution of 5.7g LiAlH4 in 110ml ether under nitrogen and the mixture was treated dropwise over 30 min with a solution of 22.4g VIIa in100 ml THF. The mixture was stirred and refluxed for 6h, after cooling decomposed with water and 20% NaOH, and extracted with benzene. Processing of the extract gave 22.7g (theoretical) of oily XIIIa.
2-(4-(heptylthio)-2,5-dimethoxy-phenyl)ethylamine(XIIIa)The reagent was prepared from 11.0g AlCl3 and 4.0g LiAlH4 in 160ml ether under nitrogen and was used to reduce similarly (like XIIIa) 17.3g VIIb; 14.9g (85%) of oily XIIIb was obtained.
Also they synthetised their dimethoxy-thiophenol from potassium ethyl xanthate in a process similar to this:
p-Methoxythiophenol (ref unknown)
This was first prepared by Gatterman by reduction of the corresponding sulfinic acid. In the present work it was prepared from p-anisidine by the Leuckart reaction. The following conditions were found to be the most satisfactory. In a 5-liter 3-necked flask equipped with a mechanical stirrer, dropping funnel and outlet tube to the hood, was placed a solution of 300g (1.9 moles) of potassium ethyl xanthate dissolved in 700 cc of water. To this solution, kept at 70 to 80°, was added slowly with vigorous stirrring a cold solution containing 123g (1 mole) of diazotized p-anisidine to which had been added enough sodium acetate to neutralise the free acid. Stirring and heating were continued for about an hour after the addition of the diazonium solution to complete the decomposition of the intermediate diazonium ethyl xanthate. The dark oil was removed from the cooled solution and the aqueous layer extracted with ether, the product obtained being combined with that first removed; this material was then refluxed for three hours with a solution of 115g of potassium hydroxide in 2 liters of 95% ethyl alcohol to which had been added 20g glucose. The alcohol was removed by distillation until the residual volume was about 300cc. This was acidified with cold dilute sulfuric acid, a few grams of zinc dust added, and the oily thiol removed by distillation with steam. The distillate was extracted with ether, the ether dried over calcium chloride, and the oil remaining after distillation of the ether was distilled under reduced pressure. The yield was 100 to 110g or 71 to 79%
This was a reference they cited but i dont have it at hand. Take care that here it is not the 1-methoxy-4-thiophenol but the 1,4-dimethoxy-2-thiophenol that is wanted. The procedure is similar but the yield is more like 50% (I dont remember exactly).
See also
Patent CS271850
ref:Collection of Czechoslovak Chemical Communications (1990), 55(3), 782-96.