karlos³
International Hazard
Posts: 1520
Registered: 10-1-2011
Location: yes!
Member Is Offline
Mood: oxazolidinic 8)
|
|
5-alkylbenzen-1,3-diol synthesis
Hello dear mad scientist colleagues!
I was thinking of a feasible route to some 5-alkylresorcinol derivatives, though most of the (free) avaible papers for it use reagents that are very
expensive or hard to get. I personally was thinking of phloroglucinol als starting material (because i have some lying around^^), protect two of the
OH groups through methylation using dimethylcarbonate, and then i have no idea what to exactlywith the dimethoxyphenol maybe i stuck to much to the
idea that i could somehow use the n-hexylbromide i also have lying around here.
Maybe somebody has some method quick to hands, as i am searching and thinking for a few days now and i just need another point of view.
The synthesis i thought of by the way would be finished by demethylation in HBr(aq) and HOAc, or alternatively using pyridine (which can make you
sterile!).
with best regards karl
|
|
|
turd
National Hazard
Posts: 800
Registered: 5-3-2006
Member Is Offline
Mood: No Mood
|
|
Not to rain on your parade, but if you can't look up the necessary literature at a university library, maybe you should start with an easier project?
It really depends on what chemicals and equipment you have access to and of course what alkyl chain you have in mind. The general procedure is
probably via an acyl derivate and then reduction or Grignard.
|
|
|
karlos³
International Hazard
Posts: 1520
Registered: 10-1-2011
Location: yes!
Member Is Offline
Mood: oxazolidinic 8)
|
|
Hello there,
time has passed and i am almost there, and yes a grignard was needed, I dont have my papers around but i used about 4,9g Mg dust, 33g 1-hexylbromide
to prepare a grignard reagent which was consequently reacted with 12g acetone (all reagents a bit over 0,2mol) in Et2O and let stood overnight, to
give after hydrolysis nearly 26g 2-methyl-2-octanol.
I reacted 14.4g of this with 15,5g syringol which is 0,1mol each in 25ml methanesulfonic-acid with a few ml dimethylsulfoxid 5hours at 50°C in an
oilbath and got after pouring on ice and extracting with diethylether only 22g of 4-(1,1-dimethylhepty)-2,6-dimethoxyphenol,where the original paper
got more than 27g in the same starting quantity, but they extracted with methylenchlorid instead. I will add this paper later, but at this point I
have a question: is it possible to reduce the phenolic hydroxy-group using AlO3(Et)3? I know alkalimetal-alkoxides can be used and i do have sodium
and dry alcohols if necessary, but I also have aluminiumisopropoxide ready for use that would be less work for me?
Thank you for may responsing, good night!
|
|
|
karlos³
International Hazard
Posts: 1520
Registered: 10-1-2011
Location: yes!
Member Is Offline
Mood: oxazolidinic 8)
|
|
Well I finished the whole synthesis more than a half year ago and simply hadnt the time to update this thread also like on another forum where I
published it first when it was done.
Here it is:
| Quote: |
First a tertiary alcohol was prepared, 2-methyl-2-octanol in a yield of nearly 26 gram made out of a grignard reagent prepared from 4,9g Mg-dust and
33g 1-hexylbromide, and after cooling reacted with 12g acetone solvated in a bit ether then let stood overnight. All reagents used are 0,2mol, solvent
used was very dry Et2O. Mg was activated using a tiny piece iodine. Was quenched on a half liter cold water with ice still in it, and not more
extracted beside the starting portion ether, dried with Na2SO4 then.
Next reaction 14,4g of 2-methyl-2-octanol were reacted with 15,5g 2,6-dimethoxyphenol (both 0,1mol) in 25ml methanesulfonic acid with a few ml DMSO as
co-solvent, for about 5hours at 50°C in an oilbath,then after quenching on ice and extraction using two portion of diethylether which was washed with
diluted NaHCO3 solution and dried then over anhydrous sodium sulfate to give 22g 4-(1,1dimethylheptyl)-2,6-dimethoxyphenol as an oil.
1,9g of this substituted phenol (67mmol) were reacted then with an alkoxide made from around 7,5g sodium metal (~0,3 mol) to give dimethylether of
target compound, effecting removal of phenolic hydroxylgroup. First try was made with isobutanol and about 7,7g sodium, the sodium weighed in a hurry,
patted dry of naphtha und cut and added fast as it oxidized in seconds. (becoming opaque on its shiny fresh cut surface)
It reacted very well anyway. After it has dissolved completely it was refluxed a half hour, let cool a bit, as the isobutoxide started to solidify, it
was poured on ice water, acidified and the isobutanol salted out, to give 1,39g of the dimethylheptylolivetol dimethylether as a visous oil, pure
enough on tlc to continue.
The second run was made using nearly 8g sodium and dry ethanol, also 1,9g starting material, and was extracted using DCM instead, and yielded this
time a nearly similiar yield of 1,44g oil.
1,44 of dimethylheptylresorcinol dimethylether from the previous reaction were dissolved in 24ml of GAA with 6ml fuming HBr added, and refluxed in an
oilbath for 8 hours, after which it let cool, then it was poured on 120ml of ice cold saturated brine in a beaker, then left to stir the turbid
solution as a brown gooey looking substance started to harden, and the substance precipiated out. Product was filtered, washed with water twice and
once with very diluted hydrogen carbonate solution to ensure its acid free, then dissolved in 20ml 10% NaOH solution, extracted with 1x10 and 1x5ml
MTBE.
The aqueous phenolate containing solution was made acidic with 15ml 30% HCl and extracted with 2x15ml portions DCM, dried over CaCl2 and distilled off
to give a yellow oil weighing 530mg, hardened on standing to a resinous solid. Melting point 85-90°C. (literature 93-95°C)
On tlc plates some impurity visible possibly its monomethylether, that would contribute to melting point and slow hardening once it got molten.
Unfortunately i dont have the rf values anymore.
Had then a look at the eluotropic serie and chose acetone/diethylether for recrystallisation and was able to raise the melting doing it four times, to
be on a par with the literature cited one now (92-95°C).
But whats left weighed only a bit around 380 milligram, i dont had the necessary small enough equipment to handle this much mechanical loss... and I
was very conscientious rinsing everything mit ether to minimise mechanical loss, but anyway.
Very inconvenient synthesis! Everything comes out just as hard to purifying oil, except the also very discolored final product because a demethylation
with HBr in AcOH really sucks in yield and purity!
The reagents used so far, as some of them aren´t that common in a home laboratory, have some characteristics that should be noted.
-Methane sulfonic acid is a very strong acid, especially when pure, it can carbonise organic materials like concentrated sulfuric acid.
-Diethylether vapours are very explosive, a grignard reaction should not attempted when ones heatplate is not spark proof or even when one has not
proper lights installed as the vapours can catch fire there, unlikely but possible especially without a fume hood.
-Magnesium especially when its fine powder can (thats what the bottle says at least) catch fire in humid air. -Sodium metal does catch fire on contact
with water and its possible even on air exposure due to air humidity. Reacts also violent with alcohols, probably very violent with undried ones.
references for reactions carried out are for the first, second and fourth reaction:
Intermediates for 5-(tertiary alkyl) resorcinol preparation US patent 4131656
US patent 4131656
and for the third reaction it was:
Suter and Weston; J.A.C.S., 61, page 232, (1939).
and Divarin Dimethyl Ether from 3,4,5-Trimethoxy -propiophenone by Yasuhiko Asahina Tokyo, Japan May 20, 1936 translated by Otto Snow and finally yet
another (Asahina Berichte 68B, page 1500, 1935, Asahina Berichte 69B, page 1643, 1936). |
|
|
|
Paddywhacker
Hazard to Others
Posts: 478
Registered: 28-2-2009
Member Is Offline
Mood: No Mood
|
|
We done, and a pity about the final yield. If you were to do the final step again would you choose a different purification method than
recrystallization?
|
|
|
karlos³
International Hazard
Posts: 1520
Registered: 10-1-2011
Location: yes!
Member Is Offline
Mood: oxazolidinic 8)
|
|
I shouldnt have chosen this method of O-demethylation, instead a cleaner and higher yielding catalyst like some AlX3 in pyridine should have been
used, beneficial in every aspect and a friend has already told me that before but I hadnt listened.
And of course if i would make the last step again, i would monitor the progress of reaction on TLC plates, it was plain stupid/lazy to left this out
considered its the only time a solid is obtained.
If done proper there is no need for excessive purification, especially not when another demethylation procedure instead of the messy HBr/AcOH one is
used.
[Edited on 19-5-2013 by karlos³]
|
|
|
turd
National Hazard
Posts: 800
Registered: 5-3-2006
Member Is Offline
Mood: No Mood
|
|
Very nice work! And an interesting route - I learned something. (Side remark: I would have tried to turn syringol into syringaldehyde, but to each his
own.)
|
|
|
caribou
Harmless
Posts: 29
Registered: 21-2-2006
Member Is Offline
Mood: No Mood
|
|
Quote: Originally posted by karlos³  | 1,9g of this substituted phenol (67mmol) were reacted then with an alkoxide made from around 7,5g sodium metal (~0,3 mol) to give dimethylether of
target compound, effecting removal of phenolic hydroxylgroup. First try was made with isobutanol and about 7,7g sodium, the sodium weighed in a hurry,
patted dry of naphtha und cut and added fast as it oxidized in seconds. (becoming opaque on its shiny fresh cut surface)
It reacted very well anyway. After it has dissolved completely it was refluxed a half hour, let cool a bit, as the isobutoxide started to solidify, it
was poured on ice water, acidified and the isobutanol salted out, to give 1,39g of the dimethylheptylolivetol dimethylether as a visous oil, pure
enough on tlc to continue.
The second run was made using nearly 8g sodium and dry ethanol, also 1,9g starting material, and was extracted using DCM instead, and yielded this
time a nearly similiar yield of 1,44g oil.
...
Suter and Weston; J.A.C.S., 61, page 232, (1939).
and Divarin Dimethyl Ether from 3,4,5-Trimethoxy -propiophenone by Yasuhiko Asahina Tokyo, Japan May 20, 1936 translated by Otto Snow and finally yet
another (Asahina Berichte 68B, page 1500, 1935, Asahina Berichte 69B, page 1643, 1936). |
Sorry, this looks like utter nonsense. Phenols are stable under these conditions. The only thing that could happen is phenolate formation.
There is no mention of such a reaction in the papers you cited. Methoxy or O,O-dialkylphosphoryloxy group can be reductively cleaved with sodium (NOT
with sodium alkoxide). The phenolic hydroxyl cannot (AFAIK).
|
|
|
karlos³
International Hazard
Posts: 1520
Registered: 10-1-2011
Location: yes!
Member Is Offline
Mood: oxazolidinic 8)
|
|
It could even cleave an MeO-group on 4-, it depends on the position in this reaction...
Theres a mention as well of this reaction in rhodiums archive.
How would you even reduce with sodium alone, liquid ammonia, or benkenser style in an amine?
The two old papers describe the sodium alkoxide reaction, the patent any other reaction ive done.
I can for sure confirm that it works!
Even if the product will be very likely coming out colored in orange, it contains no phenol anymore!
| Quote: | | I would have tried to turn syringol into syringaldehyde |
If I would make this compound again, I would do it anyway only from aliphatic precursors, the chosen route sucks, too many steps, too labor-intensive.
Seems better just to condense an a,ß unsaturated ketone like it would bee in this case 5,5-dimethyl-3-undecene-2-one, with diethyl malonate and
sodium ethoxide to give a cyclohexene carboxylic acid ester, which becomes through halogenation/oxidation and decarboxylation in only three steps a
fully aromatic molecule(like here: DOI: 10.1002/jlcr.2590070307).
|
|
|
|
![[*]](images/xpblue/default_icon.gif){kind=icon}
