Phenols can be readily converted into thiophenols by the use of P2S5 or P2S3, and there are examples of direct aromatic alyklthiolation using a phenol, an alkyl thiol, and TsOH.

So what do people think? Could this be a sytnhetically practical approach?

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-the good reverend drone

Lilienthal
Member   posted 02-02-99 12:33 PM          
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It's an old dream of mine to use vanilline as a starting compound...
Please could you give us the references for the suggested reactions (i.e. the alkylthiolation and the methoxylation of position 2)?
Regarding the alkyl thioles = mercaptanes: Considering the smell (it really is that bad), I know I won't be working with it soon.

Piglet
Member   posted 02-03-99 04:51 AM          
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Slightly off topic, but has anyone considered strygial (spellcheck someone) alcohol? I seem to remember it being 3,5 dimethoxy 4 hydroxyl allyl benzene, or somesuch. Adding an ethoxy group might be interesting...
 
rev drone
Member   posted 02-03-99 02:35 PM          
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Goddamit! Alright, now I'm pissed. Sorry for swearing in the holiest-of-holies, but this is the 3rd goddam time I've written this goddam post, and to top it all off, I screwed up majorly in the original post of this thread.
First off, I appologise. I meant to discuss thiomescaline and thio TMA analogs from vanillin, not 2-CT's. There is no practical way of putting a substituent in the 2-position that I'm aware of. However, the 4-thiopheonl would lend itself to activating its unsubstituted neighboring position more than the hydroxy would.

What I envision is a reaction involving some of the following steps (in no particular order):

*replacement of the phenolic oxygen with a thiol.
*alkylation of the thiol
*bromination of the unsubstituted 5-position, followed by a subsequent methoxylation
*most likely a knoevenhagel condensation of the aldehyde with either nitromethane or nitroethane, follwed by a reduction to the amine.

There are a few synthetic challenges here with regard to order, and the possibility of side reactions. IF one thiolates first, will the oxygen in the aldehyde be replaced? True, even if it were, the subsequent Knoevenhagel would probobly go on without a hitch, but its something to take into consideration. If one does this after the Knoevenhagel, what about the oxygens on the nitro? And one would have to proect the amine after reduction, if one planned to do it after the amine has been formed, since alkylation of the thiol would result in subsequent alkylation of any primary amine as well.

The following is a list of basic related replacements of phenolic (and other aryl hydroxy) oxygens using P2S5 (phosorous pentasulfide):

Chem.Ber.; 109; 1976; 2164-2174;
Aust.J.Chem.; 39; 1; 1986; 69-75;
Aust.J.Chem.; 38; 5; 1985; 825-833;
Aust.J.Chem.; 36; 5; 1983; 983-992;
Helv.Chim.Acta; 69; 1986; 708-717;
J.Heterocycl.Chem.; 8; 1971; 89-97;
Chem.Ber.; 81; 1948; 12,19;
Pharm.Bull.; 2; 1954; 131,135;
J.Prakt.Chem.; <2> 8; 1873; 168;
Chem.Ber.; 6; 1873; 934;
Chem.Ber.; 6; 1873; 669;
Monatsh.Chem.; 89; 1958; 685,687;
J.Amer.Chem.Soc.; 73; 1951; 4988;
J.Chem.Soc.; 1959; 2384, 2396;
Pharm.Bull.; 2; 1954; 131,135;

The following is a list of oxygen replacements with P2S5 that also involve other oxygens in the environment. With a couple exceptions (the Australians' work), it seems to be quite selective for phenolic oxygens, though there are no examples of aromatic aldehydes being selectively omitted (though aromatic ketones seem to be alright.)

Its interesting to see that the Egyptian work shows this method to be quite compatable with amany different substituents, including aromaict nitriles and acids -- which implies if the Knoevenhagel route wouldn't work, the amine could be achieved through the Mannich reaction, making the arylacetonitrile.

Egypt.J.Chem.; 37; 3; 1994; 273-282;
Aust.J.Chem.; 37; 26; 1984; 2093-2101;
J.Med.Chem.; 34; 9; 1991; 2768-2778;
Collect.Czech.Chem.Commun.; 50; 2; 1985; 393-417;
Monatsh.Chem.; 89; 1958; 685,687;

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-the good reverend drone

rev drone
Member   posted 02-03-99 02:56 PM          
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This same stuff would also be useful for maing other various thioalkylated compounds, including thionyl homologs of MDA's, MMDA-2's, etc. Here's a list of compounds from PiHKAL I forsee this technology being applicable to:
147 4-TASB 3-Ethoxy-4-ethylthio-5-methoxy-PEA
149 TB 4-Thiobutoxy-3,5-dimethoxy-PEA
151 4-TE 3,5-Dimethoxy-4-ethylthio-PEA
156 4-TM 4-Methylthio-3,5-dimethoxy-PEA
164 4-TME 3-Ethoxy-5-methoxy-4-methylthio-PEA
174 TP 4-Propylthio-3,5-dimethoxy-PEA
177 4-TSB 3,5-Diethoxy-4-methylthio-PEA
179 4-T-TRIS3,5-Diethoxy-4-ethylthio-PEA

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-the good reverend drone

rev drone
Member   posted 02-03-99 03:04 PM          
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In addition, I think this method could be used to produce the following phenthylamines and amphetamines not mentioned in PiHKAL:
4,5-Thiomethyleneoxy PEA/A
3-methoxy-4,5-Thiomethyleneoxy PEA/A
3-ethoxy-4,5-Thiomethyleneoxy PEA/A
4-Isopropylthio-3,5-dimethoxy PEA/A
4-propylthio-3,5-dimethoxy A

All of these sound quite interesting, especially the thiomethyleneoxylated compounds (the MDA and MMDA thio analogs.)

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-the good reverend drone

Rhodium
Administrator   posted 02-03-99 03:31 PM          
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Wouldn't forming the dimethylacetal protect the benzaldehyde from your PxSy?
 
rev drone
Member   posted 02-03-99 05:30 PM          
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Rh,
Adding a protecting group certainly would, but that adds two extra steps (putting it on and taking it off), which either may or may not be necessary.

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-the good reverend drone

rev drone
Member   posted 02-04-99 05:09 PM          
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The ongoing saga of 4-akylthio compounds....
I've done a little mroe research, and I've found plenty of evidense that the oxygen in the alkdeyde would indeed be readily replaced by a sulfur atom, given the chance (ref's happily made available upon request.) This makes perfect sense.

Interestingly, I've dug further, and found that phosphorous pentasulfide leaves nitro groups alone (again, say the word, and I'll post a list of articles.) This means that perhaps the best synthetic route is to react vanillin with a nitroalkane, then react it with P2S5, then synthetic routes will vary.

Thiomescaline is interesting. Ten times as strong as regular mescaline, and just as complex.

I wonder why Dr. Shulgin didn't make the thio analogs of MDA and MDMA? It looks like they're just waiting to me tried out. I wonder what kind of activity they'd have. Hm...

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-the good reverend drone

Rhodium
Administrator   posted 02-08-99 01:44 AM          
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He at least made a MMDA derivative with a sulfur in the ring. 4-T-MMDA-x something.
 
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