J.Overmann in the future - 24-5-2020 at 05:28
Hello everyone !
I've been wondering about a possible cyclisation to obtain "OTC" hydrobenzofuran by cyclisation of 2-phenoxy-ethanol previously formed by the
condensation of phenol and 2-chloroéthanol in DMSO with a base such as potassium carbonate or hydroxide.
Very little data exists around it to the best of my knowledge, as i've already been through quite a "lot" of articles and the hydrobenzofuran ring is
normally obtained by other cyclisation methods.
Then, I found a rather vague, from chinese approximative translation of a method, that would use a mixture of lewis acids : MnCl2 and ZnCl2 in a (5:1
ratio and around 10 to 20%mol based on the substrat). A direct heat of the 2-phenoxy-ethanol with those would lead to the distillation under vacuum of
the desired compound.
My other, unreferenced educated guess would be a rather stupid deshydratation of the 2-phenoxy-ethanol by treatment with phosphoric or concentrated
sulfuric acid and use of the same distillation.
What do you guys think about the feasibility of such procedures ?
Thank you for your help !
Here is a quote from the reference i found on the net :
"The invention discloses a synthesis method of 2,3-dihydrobenzofuran and belongs to the field of organic chemical synthesis. The preparation method
comprises the steps that sodium phenate and 2-chloroethanol are used as raw materials, copper chloride and ferric chloride mixed solid is added as a
catalyst, cooling is carried out after mixing, backflow and reflux reaction, an organic layer is collected, a sodium hydroxide solution is used for
washing, 2-phenoxy ethanol is obtained, the 2-phenoxy ethanol is mixed with zinc chloride, manganous chloride is added as a catalyst, heating and
reflux reaction are carried out, the sodium hydroxide solution is added for washing, reduced pressure distillation is carried out, fraction at the
temperature of 88-90 DEG C is collected, and the 2,3-dihydrobenzofuran is obtained. According to the method, the copper chloride and ferric chloride
mixture and the manganous chloride are used as the catalysts, the reaction technology and the reaction condition are optimized, the reaction
temperature can be effectively decreased, reaction time can be shortened, the produced reaction by-products can be reduced, reaction efficiency can be
improved, and the high economic benefit is obtained."
HU HAIWEI / DING LIANG / YAN YONGPING / ZHENG HUI / YAN HUI
2016
Pumukli - 25-5-2020 at 09:26
Interesting idea. I could only find the reference what you already found. To say the least I doubt if it is any good.
I question the method they vaguely sketched for the synthesis of the phenoxy-ethanol to start with. I think if you mix sodium-phenate and
2-chloroethanol they should react without much additional catalyst. The solvent may not be obvious choice but I somehow doubt that this reaction would
require ferric-chloride/zinc-chloride mixture. Anyway, it is a Williamson ether synthesis.
The cyclisation part - I don't know.
Is dihydrobenzofuran such a useful thing to have that is worth tinkering with such a vague patent in the hope of preparing it?
J.Overmann in the future - 9-6-2020 at 05:47
Well, I question this ref too. I meant they mentionned such mixture of catalysts for the cyclisation part, not the Williamson part, obviously you
don't need it.
I was just curious about it, I thought that a two step and rather OTC and uneventful synthesis as regards security would be of value here. I
personnaly don't want to use other methods I know because we loose the beauty of OTC and simplicity. But yes I could prepare it anyway in another
fashion.
Methyl.Magic - 10-6-2020 at 13:42
Yeah it should work wellno need of catalyst here, just use the correct poal aprotic solvent like DMSO, altrough it could wok in alcohol too.
Deprotonate the phenolate under inert atmosphere and then do the reaction.
After that you can brominate with ZnCl2 or FeCl3 as catalyst and finally cyclize with magnesium in THF (yield above 80%, tested myself).
J.Overmann in the future - 14-6-2020 at 00:19
Thanks Methyl.Magic for such insight ! Very helpful 
Just a question, you do brominate the remaining alcohol (I suppose HBr(aq) and the fore-mentionned cat) after the williamson but as for the
cyclisation part in THF with magnesium, do you infer that you also brominated the aromatic cycle on the ortho position so you initiate a grignard that
cyclize into the benzofuran ?
Methyl.Magic - 15-6-2020 at 04:03
Yes this is exactly like that.
For the bromination or chlorination.
Chlorination : thionyl chloride/pyridine gives excellent yields ! Or POCl3
Bromination : Yes HBr probably in acetic acid will give the brominated product.
The main problem here is bromination of hte ortho without para. You should start with o-bromophenol, commercially availaible. Otherwise you have to
separate isomer.
IMO I'll start by bromination of phenol. Maybe you can maximise the ortho isomer using the Magnesium phenolate. Magnesium have a ortho-directing
ability.
Nice luck !
[Edited on 15-6-2020 by Methyl.Magic]