Sciencemadness Discussion Board

Selective O-alkylation of bis(4-hydrophenyl)disulfide

Klute - 1-4-2008 at 14:56

I have a dilema.

I want to selectively alkylate the phenol groups on bis(4-hydroxyphenyl)disulfide, without cleaving and alkylating the disulfide bond.
I was lucky enough to find an example where this is done, with alkyl halides in DMF using NaH as a base. The reaction iproceeds in 30min, they use chloromethyl methyl ether as the alkyl halide, while i plan using short aliphatic chains. [preparation 12, preparation of 4-(methoxymethyloxy)phenyldisulfide in patent US 5510358 ]
I was reassured that the disulfide bond would not cleave without any added reducing agent (zn, sulfites), and that they usded NaH just because they always use it, and that K2CO3 should work just aswell. Until i crossed this article where a disulfide is cleaved, and alkylated with a complex alkyl halide by simply heating a few hours in DMF in presence of K2CO3 [ scheme 2; (7) being the disulfide and (6) the alkyl halide. Details page 1584, 1,3-Bis{[5-(5-amino-1,2,4-thiadiazol-3-yl)thio]-3-oxapentylthiomethyl}-
benzene (8)..

Ok, the first patent uses the same substrate as i will (but it's a patent!), just a more reactive alkyl halide. Is it the long heating time that cleaves the disulfide in the second article? Or the use of K2CO3?
I guess I will use NaH the first time, and i will have to use the most reactive alkylating agent i can get, apart from DMs i don't want to handle. So MeI instead of TMP for methylations, and EtI or TsOEt instead of EtBr, even though it going to much more expensive.. So i can shorten reaction times, and use the less excess of alkylating agents as possible. But could K2CO3 be substitued for NaH? I don't have some at hand and would be bothered buying some just for that, considering the small scale i plan doing this on.

Any comments, advise welcome. And could someone with practical experience tell me how stable aromatic disulfides are (reactions will be done under argon, but should i directly use after the isolation, or can i wait to compare different reaction conditions and combine products before passing to the next step?), and if they smell as bad a the thiols? i guess not, but...

EDIT: Strangely, Wikipedia states that NaH reduces disulfide bonds, for what it's worth... DMF possibly diminishes the reducing properties of NaH?

[Edited on 2-4-2008 by Klute]

jizmaster - 1-4-2008 at 16:06

I think it will be ok, was going crazy trying to figure out what was going on in that Korean chem soc paper until I eventually looked more carefully and saw this:

'S-alkylation of bis(5-amino-1,2,4-thiadiazolyl)-3,3'-disulfide (7) was performed at the 3-position of 7 in the presence of K2CO3.'

It's a nuclephilic attack by the ring sulfurs on the alkyl chlorides, if you look you can open the ring and break the disulfide bond and use that sulfur to make the same ring, it's sort of symmetrical. Still trying to work out the mechanism though...

K2CO3 should work fine by the looks of it. NaH may reduce disulfides but i guess it's probably really slow.

Nicodem - 2-4-2008 at 07:04

Here are a couple of references for the O-alkylation of bis(4-hydrophenyl)disulfide:

With bromoacetone/NaH/DMF:
Organic & Biomolecular Chemistry, 4 (2006) 4514-4525. DOI: 10.1039/b612235c
Bioorganic & Medicinal Chemistry Letters, 16 (2006), 49-54. DOI:10.1016/j.bmcl.2005.09.060

With BnCl/K2CO3/DMF: WO2006010629

In chemical abstracts there is also a conference report where O-methylation with MeI/K2CO3/acetone at 35°C is used to get bis(4-methoxyphenyl)disulfide in 66% yield (Chem. Abstr., 142 (2004) 355083; no other details in the abstract).

Klute - 2-4-2008 at 07:38

Quote:
It's a nuclephilic attack by the ring sulfurs on the alkyl chlorides, if you look you can open the ring and break the disulfide bond and use that sulfur to make the same ring, it's sort of symmetrical. Still trying to work out the mechanism though...


Well, i have requested a few papers in the ref forum dealing with this reaction, direct 2 step synthesis of thioethers from disulfides and alkyl halides, can work with diselenides also, were they use a sulfite source (dithionite, sodium formaldehyde sulfoxylate, sodium thiosulfate) to cleave the S-S bond and subsequently alkylate it.
The propose a SET mecanisme, were the generated SO2.- radical attacks the disulfide bond forming an ArS- anion, which is alkylated by the alkyl halide, and a ArS. radical that furtherly reacts with another sulfoxylate radical ,forming SO2 and another thiolate anion.
It is also possible the sulfite cause homolytic cleavage of the R-X bond, giving a alkyl radical and halide anion, the radical attacking a disulfide bond to form a thioether and a thiolate radical, etc etc:

Sulfite-Promoted One-Pot Synthesis of Sulfides by Reaction of Aryl Disulfides with Alkyl Halides
Ri-yuan Tang, Ping Zhong, Qiu-lian Lin
Synthesis 2007, 85-91
DOI: 10.1055/s-2006-950363

similarily:

Reduced Species (HSO-2, SO2-2) Promoted One-Pot Efficient Synthesis of Phenyl Alkyl Selenides
Ri-Yuan Tang, Ping Zhong , Qiu-Lian Lin
Chinese Journal of Chemistry (4) 25; 4558 - 561 (2007)
DOI:10.1002/cjoc.200790104


Theres also this article were they simply use Zn in DMF followed by addition of alkyl halides to acheive the same thing. At first, i was surprised Zn alone (w/o acid) could do the job, but apparently it should work enough, and could avoid me making Rongalite.

EDIT: Thanks for those ref Nicodem. I guess the particuliar substrate used in the article is more easily cleaved under such conditions, and that even if it's an equilibrium, with bis(hydroxyphenyl)disulfide the base and alkyl halide quickly get consumed before causing too much cleavage/S-alkylation. I will limit the exces uqsed out of precaution though. Any remaing substrate should be more easily removed that thioethers (dilute base wash). I don't want to do a coluum purification after each step.

EDIT2: OK, i gave up going through the 171pages of the patent, as it's reconized as a image and not text, so no searching.. I guess i'm going to follow the procedure detailed in the first patent using NaH, and perhaps try with K2CO3 after to compare. I figured out i could use NaH for a lot of other things, such as alkoxide and enolate formation, and it's not that expensive (13E 100g of 60% dispersion)... We will see how it goes.

And can anyone guide me as to the stability of hydroy-/alkoxydisulfides? I'm thinking of directly using a crude hydroxyphenyldisulfide, which would containg at most 10% diphenylsulfides and chlorophenols. I know the chlorophenols could alkylate the hydroxy's to some extent, but their small amount and reactivity compared to the alkyl halide should minimize that side reaction.

[Edited on 2-4-2008 by Klute]