Yet another theoretical 2C-H synthesis, ChimimanieWell after some research in this area this is what I found.
This road look feasible, but it is not tested yet. The scheme I use is the same as poix proposed but it reduce to the hydroquinone and methylate in two steps, its easier like that and better I think, in fact reduction of the quinone to the hydroquinone may be view as a workup of the first reaction since its only a wash with aqueous hydrosulfite.
This synthesis may not work (but I think it will, prove me wrong), use no watched chemicals beside benzoquinone (which must be made from hydroquinone) and acetic anhydride and probably does not give stellar yield, i think it is for small scale manufacture of 2cb only, not for 1000+ doses reaction. Theoretically I think it is the shortest synthesis of 2C-H starting from hydroquinone (with the aryne road of course).
Well some theoretical background:
The ideal reaction would be reaction of quinone with beta-alanine to yield beta-ethylamine benzoquinone, but this will not work. Why? because the silver/persulfate oxydation transform amine into aldehyde[1]. So we must protect the amine. We can't protect it with formic, because formyl is easily removed by oxydation. We can also protect it with phtalimide, but I have not searched in this direction. Trifluoroacetic anhydride could be used, the last step (hydrolysis) would be high yielding with it[6], but it is expensive. I choose acetic anhydride. I hope than the amide will be stable in this oxydative medium, I don't know because in ref [1] they didn't speak of amide but I think so.
The alkylation proceed from a decarboxylation and generate radicals which then are scavenged by benzoquinone and alkylate it. Loss of radicals or polyalkylation are possible, read the orgsyn ref [9]. I used the orgsyn ref method in hope there is no need to use one of the variant that are in the litterature (the references of these variants are in the org syn article [9]) which use sometimes high quantity of silver and excess of acid. If this one does not work one can play with the ratios of acid/AgNO3/BQ but I think it is useless to stay with that road if it doesn't work, I will post a second road which is more reliable (ie: with no doubt that its decarboxylative alkylation work) than this. Anyway we will see, maybe this one work. (it should!
)
The second reaction is easy, it can be considered like the work up of the first, it is a simple quinone to hydroquinone reduction by a Na2S2O4 wash, with much ref covering it in the litterature, no problem.
Third reaction is an alkylation. Medium is acetone, alcohol nor water can't be used here because of the risk of hydrolysis of the amide. I hope this will not occur too much in acetone. Hydrolysis of the amide at this step would lead to alkylation of the free amine which is a lost of reactant.
Fourth reaction is an hydrolysis of the amide, the yield are not great for this step, they would be better if we used trifluoro-acetic anhydride[6]. An high yield hydrolysis of amide is welcome.
Note: after the second reaction, if the amide of the free hydroquinone compound (B) is hydrolized, we have got 2-(2,5-dihydroxy-phenyl)-ethylamine. This compound is not stable and accordingly to ref [8] it will freely oxydise itself to 5-hydroxy-indole in about 90% yield if stirred at RT in an open vessel for 10hrs. It can then be recrystallized from ether. This indole can be used for the synthesis of bufotenine or 5-MeO-tryptamine compounds.
Experimental:Precursors:Beta-alanine: see post
Post 267363
(poix: "Re: alkylation of quinones", Novel Discourse)Acetic anhydride can be synthetised from acetyl chloride and sodium acetate or with a ketene lamp, UTFSE.
Benzoquinone: see
https://www.thevespiary.org/rhodium/Rhodium/chemistry/benzoquinone.html
, I recommend to use the chlorate/V2O5 method or the sodium nitrite/O2 one, it is very important to get quinone(bright yellow) and not quinhydrone(metallic green).
Iodomethane: see
Post 301629
(Antoncho: "Two tried-and-true ways to make MeI !", Chemistry Discourse)N-acetyl-beta alanine: from [2]This is the synthesis of N-acetyl-alpha alanine, it works good (tried) on beta-alanine too, same synthesis, substitute beta-alanine and Dl-alanine.
DL-Alanine (89.1 g., 1 mole) is placed in a 2L Erlenmeyer flask provided with a calcium chloride drying tube attached to the flask through a ground-glass joint. The amino acid is mixed with 900 ml. of c.p. glacial acetic acid,and brought to the boil, with gentle agitation, on an electric hot plate. The mixture is removed from the hot plate to cool for a minute or two, and 150 mL. (1.5 mole) of c.P. acetic anhydride is carefully added in portions so as to avoid superheating and explosive boiling. The resulting solution is returned to the hot plate, brought to the boil, held at this point for 2 min. longer, and then allowed to cool to 25° at room temperature. The slightly yellowish solution is then evaporated in vacuo at 40° to a syrup and the residue treated several times with water followed each time by evaporation in vacuo at 40°. After the final evaporation with the aid of benzene
(Chimimanie's voice: toluene can be substituted) to remove the last traces of water, the syrupy residue is taken up in the minimum quantity of dry ethyl acetate and the solution chilled. On scratching or seeding, the acetyl-dL-alanine rapidly crystallizes. After standing for 18 hr. at 5°, the crystals are filtered rapidly with suction, and washed with dry ether which removes the last trace of yellow color. On drying in vacuo at 25° the yield of pure, white crystals of acetyl-dL-alanine is 10.5 g., or 80% of the theoretical; m.p. 136°.
Recovery of silver: [7]Considerable quantities of silver iodide-silver oxide residues sometimes accumulate in the laboratory, for example, in methylation studies involving the use of methyl iodide and silver oxide. While silver alone is usually recovered from silver residues, iodine is valuable enough to warrant its recovery when the residue contains a large proportion of silver iodide. In the method described, the presence of silver iodide and of silver salts soluble in concentrated aqueous ammonia is assumed. If significant quantities of contaminating salts, such as silver sulfide, are present, suitable modification is required.
Procedure: A) Preliminary treatment of residue:Ag2O + 4 NH3 + H2O -> 2 Ag(NH3)2OH
The residue containing silver iodide is freed from organic matter by extraction with a suitable solvent, dried, and ground to pass a 40-mesh sieve. The powdered residue is shaken with sufficient concentrated ammonia (sp. gr. 0.90) to dissolve all soluble silver salts. The suspension is filtered on a Buchner funnel and the filtrate (1) is reserved for subsequent recovery of silver by reduction with sodium dithionite solution.
The insoluble silver iodide is washed with water on the filter, dried, and weighed. (It is desirable to know the weight of silver iodide because a subsequent reaction involving the reduction of iodic acid with sodium dithionite requires exact quantities.)
B) Recovery of silver:AgI + Cl2 ---aqua regia---> AgCl + ICl
AgCl + 2 NH3 -> Ag(NH3)2Cl
2 Ag(NH3)2Cl + Na2S2O4 + 2 H2O -> 2NaCl + 2Ag + 2(NH4)2SO3
The powdered silver iodide (40-mesh) is treated with excess aqua regia (under hood). A solution consisting of 81 mL of concentrated nitric acid (sp. gr. 1.42) and 216 mL of concentrated hydrochloric acid (sp. gr. 1.19) is suitable for each 100 g. of silver iodide
*. The reaction proceeds vigorously but not violently. The mixture should be shaken frequently for 5 minutes until the initial vigorous reaction has subsided. The suspension is then heated gently on the steam bath for 25 minutes, with occasional shaking
**. The contents of the reaction vessel are then diluted with 330 ml. of distilled water and cooled in ice. The silver chloride is filtered on a Buchner funnel and washed with distilled water on the filter. The filtrate (II) is reserved for recovery of iodine. Silver chloride obtained in the reaction is dissolved in concentrated aqueous ammonia and combined with the previous ammoniacal filtrate (I)
***. This solution is treated with an excess of a 6 per cent solution of sodium dithionite, (ammonium formate works too) which quantitatively precipitates pure silver as a grey powder. The silver is washed with distilled water and dried. This method of recovering silver from silver chloride appears preferable to reduction with zinc or by other agents involving heterogeneous reactions.
* The quantities given in the subsequent description apply to 100g-lots of silver iodide.
** If the silver iodide contain no lumps, this treatment suffices for practically complete conversion to silver chloride. However, a test for completion of the reaction may be made by removing a small quantity of the precipitate, which after washings with water should all dissolve in concentrated ammonia solution.
*** Any residue remaining undissolved in ammonia should be treated again with aqua regia. Ammoniacal silver chloride solutions should not be allowed to stand too long before precipitating the silver since some insoluble material separates, which, on occasion, has produced violent explosions.