Author Topic: protecting an amine group  (Read 5778 times)

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agirl

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protecting an amine group
« on: March 05, 2001, 09:42:00 AM »
My aim is to synthesis 2,5-dimethoxy-4-(2-fluoroethylthio)phenethylamine; 2-CT-21. Unlike Shulgin, I want to react the molecule with 1-bromo-2-fluoro ethane after the whole nitrostyrene reduction bit. The only problem is I am having trouble decided what the best molecule would be to protect the amine group. Has anyone any idea's? I was thinking of ethylene glycol, but to be honest my knowledge of this kind of thing is lacking.
By the way, I am currently messing around a bit with different variations of the Urushibara nickel catalyst to reduce nitrostyrene. If anyone is interesting in the results I can let them know.

Osmium

  • Guest
Re: protecting an amine group
« Reply #1 on: March 05, 2001, 11:06:00 AM »
Insert that fluoroethyl group before preparing the nitrostyrene. Thiophenols are prone to oxidation, protecting and deprotecting the amine are another two steps which you could avoid, and I haven't seen any examples of thiophenol-containing benzaldehydes being used in nitrostyrene preparations and reductions. I don't know if they would work or not, but avoid all those uncertainties and alkylate the thiophenol at the beginning of your synth.

moo

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Re: protecting an amine group
« Reply #2 on: March 06, 2001, 12:24:00 PM »
Hasn't trifluoroacetic anhydride been used for that purpose? I think the thiophenol route would still be better.
And please tell us more about your experiments, surely many people would appreciate more information on Urushibara hydrogenations...  :P

smiley_boy

  • Guest
Re: protecting an amine group
« Reply #3 on: March 14, 2001, 06:24:00 AM »
agirl,

I'd have to agree with Os on this. It just makes more sense to alkylate before rather than after.

Still, if you're absolutely intent on doing the alkylation later, then I'd suggest reacting the amine with phthalic anhydride, then deprotecting it with hydrazine.

So what is your synthetic route here then? It sounds like you have something particular in mind. Please, please, please tell me you're investigating a route using benzoquinone as the starting material - I always wondered why this procedure showed so much promise for 2C-T-1, but a modified version was never even looked at for higher analogs. It just seems like such a terrible oversight, especially since it looks like it could be a great improvent over other synthetic procedures.

Otherwise, have you looked at those Czech procedures using benzyl cyanides during the early 1990's? I always thought that looked decent as well...

If you need any more information, just ask...

yellium

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Re: protecting an amine group
« Reply #4 on: March 14, 2001, 02:25:00 PM »
Benzoquinone only works in 2C-T-1 because there are methyl groups all over the molecule :-). If you're really desperate, you could try to exploit the differences in reactivity of the thiol group and the hydroxyl groups by first alkylating 2,5-dihydroxythiophenol with 1 equivalent of your alkyl iodide/bromide, then adding 2 equivalents of methyl iodide after an hour or so, and then reflux for a night. Workup as usual, and I would carefully distill the product obtained.

(if you used EtI/EtBr, you would end up with tweetio-precursors of 2ct2; I would guess that propyl or isopropyl-tweetios are inactive. But YMMV.)

smiley_boy

  • Guest
Re: protecting an amine group
« Reply #5 on: March 16, 2001, 07:36:00 AM »
yellium,


Benzoquinone only works in 2C-T-1 because there are methyl groups all over the molecule :-). If you're really desperate, you could try to exploit the differences in reactivity of the thiol group and the hydroxyl groups by first alkylating 2,5-dihydroxythiophenol with 1 equivalent of your alkyl iodide/bromide, then adding 2 equivalents of methyl iodide after an hour or so, and then reflux for a night. Workup as usual, and I would carefully distill the product obtained.



I guess I was too vague in what I was proposing. I figured from the details I gave, the route would be a bit more intuitive that it turned out to be. Here's an example of what I had in mind, illustrated for 2C-T-7:

1) benzoquinone + Na2S2O3 -> sodium thiosulfuric acid S-(2,5-dihydroxy-phenyl ester)

2) sodium thiosulfuric acid S-(2,5-dihydroxy-phenyl ester) + (CH3)2SO4, or CH3I -> Thiosulfuric acid S-(2,5-dimethoxy-phenyl) ester O-methyl ester

3) thiosulfuric acid S-(2,5-dimethoxy-phenyl) ester O-methyl ester + Zn -> 2,5-Dimethoxy-benzenethiol

4) 2,5-dimethoxy-benzenethiol + n-Pr-Br -> 1,4-Dimethoxy-2-propylsulfanyl-benzene

From there, its the standard Vilsmeier-Haak formylation, then Knoevenagel condensation, then reduction.

Note the modification: the hydroquinone is methylayted, but the sulfonate acts as a protecting group, ensuring that the thiol remains unalkylated. Treating the methylated compound afterwards with Zn will cleave the S-S bond, yielding 2,5-dimethoxythiophenol. From there, one may alkylate with whatever alkyl halide, sulfate ester, or tosylate one desires to use.

So, demethylation of the sulfur isn't necessary - just reduce the thiosulfonate substituent after alkylating the -OH groups.