Sciencemadness Discussion Board

Synthesis of 4-thioanisidine

Boffis - 17-12-2017 at 09:05

4-thioanisidine or p-methylmercapto-aniline is an important component of azo dyes and I would like to prepare some but how?

The obvious route is probably from thioanisole which can be prepared by reducing benzene sulphonyl chloride and then methylating the resulting benzene thiol. This could then be nitrated to the mono nitro compound and then reduced to the target compound. There are a few problems here however:
1/ I don't have any benzene sulphonyl chloride or the chlorosulphonic acid to produce it.
2/ the nitration of the thioanisole is likely to yield a mixture of 2 and 4 isomers,
3/ with many steps the final yield is likely to be small.

So I was wondering if it can be produced from either 4-nitroaniline or 4-nitrochlorobenzene? In the former case I was thinking along the lines of a diazonium reaction to a thio, methylate and reduce to the target compound. Problems: diazonium sulphide type compounds are notoriously prone to spontaneous explosions.

With the latter compound there are published procedures for the condensation of hydrosulphide and disulphides with 2 and 4 nitrochlorobenzene (preparation of orthanilic acid in Shirley). The disulphide route seems best as the hydrosulphide may reduce the nitro group in the progress. The problem then is the reduction of the disulphide link without the nitro group or if they are both reduced to give 4-mercaptoaniline is it then possible to selectively methylate the mercapto group (and not the amine)?

One final possibility is the reduction of sulphanilic acid or sulphanilamide but even if possible leaves the same problem of selective methylation. Would acetylation of the amino group help protect it from methylation? Would methylation under strongly basic condition help prevent amine methylation?

I have done some on line searching but surprisingly I didn't find anything useful in spite of the importance of this compound to the dye industry. If there are any patents they must be very old. I did find several preparations for sulphanilamide that suggest that it may be possible to prepare this target compound from acetanilide+ chlorosulphonic acid and then reduce the sulphonyl choride to the mercaptan followed by methylation and de-acetylation but this process requires chlorosulphonic acid again.

Can anyone provide any useful enlightenment, experimental details or comment?

Sigmatropic - 17-12-2017 at 09:28

perhaps through a reaction of aniline on dimethyl disulfide, an analogous reaction is mentioned on the wikipedia page: "DMDS is used in the preparation of 4-(methylthio)phenol which is used in the production of various pesticides. DMDS and chlorine are reacted with borontrifluoride phenolate to produce 4-(methylthio)phenol." https://en.wikipedia.org/wiki/Dimethyl_disulfide

Metacelsus - 17-12-2017 at 10:35

Thioanisole nitration probably won't work at all, since I would expect the thioether to be quickly oxidized. However, there's an interesting alternate route involving dimethyl sulfoxide. I've attached some Reaxys results.
Attachment: reaxys.pdf (509kB)
This file has been downloaded 523 times

[Edited on 12-17-2017 by Metacelsus]

CuReUS - 18-12-2017 at 06:23

Quote: Originally posted by Boffis  
So I was wondering if it can be produced from 4-nitrochlorobenzene?

4-nitrochlorobenzene to 4-nitrothioanisole -http://pubs.acs.org/doi/10.1021/jo00013a037
4-nitrothioanisole to 4-thioanisidine -http://pubs.acs.org/doi/10.1021/ol403079x

Boffis - 18-12-2017 at 07:27

Thank you for the help guys, there are some very interesting reactions here hat I have never come across before but they give me plenty scope to try.

@CuReUS, in the second paper from organic letters they use a designer surfactant, do you think that this is vital to the reaction or do you think I could use other non-ionic surfactants like Tween or one of the polyol/ polyether polymers?

[Edited on 19-12-2017 by Boffis]

Sigmatropic - 18-12-2017 at 10:46

You might also be interested in: http://pubs.acs.org/doi/abs/10.1021/jo00273a044
Initial hit said they obtain a 24% yield of 2-thioanisidine along with 48% of 4-thioanisidine from dimethyldisulfide, AlCl3 and aniline. Whereas with CuI they get 33% of the ortho and 32% of the para isomer. The products are apparently seperable by fractional distillation.

[Edited on 18-12-2017 by Sigmatropic]

CuReUS - 19-12-2017 at 08:15

Quote: Originally posted by Boffis  
@CuReUS, in the second paper from organic letters they use a designer surfactant, do you think that this is vital to the reaction or do you think I could use other non-ionic surfactants like Tween or one of the polyol/ polyether polymers?

Since the reaction is elementary(nitro reduction using Zn metal), I think you could get away with using other surfactants.You might even be able to run it without any surfactant at all.You would get a reduced yield though:(

Boffis - 19-12-2017 at 09:13

@ Sigmatropic; many thanks for your lead too, this looks like the way to go. I just have to work out how to make dimethyl disulphide without driving out my neighbors :). Interestingly there is a reaction that I have been mean to try for years but the byproduct is methyl thiol but now I am looking at possibly carrying out the reaction in a closed vessel with a scrubber containing iodine solution which oxidises it to the disulphide. The alternative I guess is to react Na2S2 with methyl iodide. Does anyone know if the smell of the disulphide is a bad as the mono thiol?

@ CeReUS; I'll have ago at this sometime, I have some Tween 20 so I'll try this first.

Just as a side thought, does anyone know how to prepare the 3-thioanisidine. In the JOC paper linked by CeReUS above the authors tried the same reaction on 3-chloronitrobenzene but the reaction failed and gave a mixture of reduction products but the chlorine remained largely intact.

CuReUS - 19-12-2017 at 19:15

Quote: Originally posted by Boffis  
does anyone know how to prepare the 3-thioanisidine.

1.synthesis of 1-methylsulfanyl-3-nitrobenzene-http://pubs.rsc.org/en/content/articlelanding/2013/cc/c3cc41...
2.reduction to m-nitrothioanisidine -http://onlinelibrary.wiley.com/doi/10.1002/adsc.200700070/fu...