Sciencemadness Discussion Board

Paracetamol --> 2,5-dimethoxyallylbenzene

Intergalactic_Captain - 14-4-2007 at 14:41

I realize that there are signifigantly cheaper, easier, more straight-forward methods than what I am proposing for this, but bear in mind that ALL necessary reagents can be obtained from grocery and hardware stores. For steps involving fancy glassware, I'm reasonably certain that a few wine bottles and enough copper tubing to make a leibig condenser and a wide-bore reflux condenser would do the job. Oh, and a quality GE hotplate is a must. This is basically going to be my summer project, and I figure the unnecessarily long procedure will keep me busy for quite a while. The roadmap is laid out in the manner that I figured would allow for the least amount of side reactions.

I'm still working on tracking down a couple of journal articles, but every procedure I am listing is either validated or supported strongly by theory...Now, can anyone point out anything blatantly wrong, or find some area where I could use improvement? I am particularly worried about the p-aminophenol extraction, as I am still not entirely sure as to how to isolate it.


Necessary Reagents (In order of necessity):
Paracetamol
NaOH
Methyl Nirtrate
-MeOH nitrated in H2SO4/NH4NO3
Sodium Nitrite
HCl (37-41%)
Allyl Bromide
-Allyl Alcohol brominated by NaBr/H2SO4, not sure of specific procedure to use as of yet...
-Allyl alcohol produced by reaction of Oxalic Acid with glycerine, with formic acid byproduct saved for future use.
H2SO4 - Rooto is fine

Miscellaneous solvents:
Methanol, Anhydrous
Dichloromethane (distilled Jasco Paint remover gel crap)
Toluene
Acetone


Paracetamol --> p-aminophenol
Following the extraction and purification of the paracetamol, it is hydrolyzed in a solution of NaOH by heating on a boiling water bath for ~30 minutes. I am still looking for the original article regarding this procedure, I found it referenced in Spectrochimica Acta Part A 60 (2004) 1861–1864, an article dealing with microwave deacylation of paracetamol for analytical purposes.
Following the hydrolysis, the solution would be transferred to a large separatory funnel and washed a couple times with DCM. The mixture would then be made acidic by means of HCl (though H2SO4 might also be used), and the resulting phenol extracted several times with more DCM. The pooled extracts would be evaporated, and used as-is for the next step. The only thing I'm worried about with this is the amine group forming an acid salt and remaining in the aqueaous layer in the final extraction step...Any input here?

p-aminophenol --> p-aminoanisole
The crude p-aminophenol is dissolved in slightly over the molar amount of 50% NaOH sol'n and stirred at room temperature. A 1.1-1.2 molar amount of methyl nitrate dissolved in methanol is added slowly, so as to avoid rapid temperature fluctuations. The mixture is slowly heated on a waterbath, the bath gradually boiling and then held for a couple hours.
After this, the solution is cooled and extracted thrice with toluene. The pooled extracts are rinsed several times with dilute NaHCO3 and saturated NaCl solutions. The toluene is evaporated under vaccum, and the remaining residue used as-is for the next step. The methylation procedure I chose is based on availibility of precursors matched to personal choice - I'd rather handle an explosive than one of many insidious carcinogens.

p-aminoanisole --> p-methoxyphenol (should probably weigh the above-formed anisole first to calculate necessary amounts of reagents)
To the crude anisole is added enough 3M HCl to afford dissolution. Following this, the necessary amount of NaNO2 sol'n is added in accordance with a standard diazotization procedure. The reaction is allowed to proceed for some time on ice, and is then heated and stirred to afford decomposition of the diazonium salt to the phenol.
As for workup, the mixture is extracted several times with toluene, and the pooled extracts washed several times with dilute NaHCO3 and conc. NaCl solutions. The toluene is then extracted thrice with NaOH (unsure of concentration here), the aqueous phases pooled. These are washed with a NP of choice, then finally acidified and extracted into DCM. The DCM is evaporated, leaving p-mehtoxyphenol.

p-methoxyphenol --> p-allyloxyanisole
The p-methoxyphenol is dissolved in a slight molar excess of 50% NaOH and stirred, to which is added ~1.1-1.2 molar amount of allyl bromide. This is stirred and heated for several hours, then cooled and added to a sep. funnel.
The reaction mixture is extracted thrice with toluene. The pooled extracts are washed thrice with ~10% NaOH, followed by NaHCO3 and NaCl. The toluene is removed under vaccum, and the residue used for the next step.

p-allyloxyanisole --> 2-methoxy,5-hydroxy-allylbenzene
The above residue is refluxed for 3-4 hours to facilitate the claisen rearrangement. It is then cooled and basified with NaOH, and washed thrice with DCM. The aqueaous phase is then acidified, and extracted thrice more with DCM. The pooled 2nd stae DCM is evaporated and the crude product used directly.

2-methoxy,5-hydroxy-allylbenzene -->2,5-dimethoxyallylbenzene
The above product is combined with a slight molar excess of 50% NaOH and methylated as earlier with methyl nitrate.
The reaction mixture upon completion is washed extracted several times with toluene. The pooled extracts are then washed several times with NaOH, followed by NaHCO3 and NaCl solutions. The toluene is then dried with MgSO4 and evaporated under vaccum to leave the (should be) relatively pure product.

I'm sure from here the product could be fractionally distilled for further purification. I'm probably not going to go through the trouble, though, as it should be pure enough for the next step...Let's just say that if anyone found this post thought provoking, it may be beneficial to read up on Ritters work in 1948 (JACS, i believe) on the preparation of secondary acetamides from olefins and acetonitrile. Apparently, a little water is all it takes to hydrolyze them to the corresponding primary amine.

What's more, the acetonitrile could be prepared from acetic acid and urea, or acetic acid and ammonia, or from one of any number of ways that proceed to acetamide. There's a thread somewhere on this board that deals with the production of acetonitrile from acetamide and acetic acid (very simple, think mix+distill).

So, in essence, I've got a theoretical roadmap using cheap and extremely availible reagents (aside from NaNO2, but I'm sure that in an act of desparation it could be recrystalized from sausage curing powder) for the production of 2,5-dimethoxyallylbenzene from tylenol. Cheap, dirty, needlessly overcomplicated...I can't wait till this semester's over and I can get back to my lab.

Nicodem - 15-4-2007 at 00:50

Quote:
Originally posted by Intergalactic_Captain
p-aminophenol --> p-aminoanisole
The crude p-aminophenol is dissolved in slightly over the molar amount of 50% NaOH sol'n and stirred at room temperature. A 1.1-1.2 molar amount of methyl nitrate dissolved in methanol is added slowly, so as to avoid rapid temperature fluctuations. The mixture is slowly heated on a waterbath, the bath gradually boiling and then held for a couple hours.

What is the magic that prevents the amino group from getting methylated? You should methylate paracetamol first and then hydrolyze (but use no more than 1.2eq of NaOH as the acetanilidic hydrogen can also get deprotonated by NaOH). Also, methyl nitrate might be a bit too slow to alkylate at room temperature. You could use MeI, MeBr, (MeO)2SO2, (MeO)3PO, dimethyl oxalate or some other methylating reagent less prone to explosive decomposition (while some are just as preparable from OTC materials).
Quote:
...The DCM is evaporated, leaving p-mehtoxyphenol.

It seems unbelievable wasteful to do all this to get p-methoxyphenol which is accessible in one simple step from hydroquinone (totally OTC), methanol and H2SO4 (also OTC).
Quote:
p-allyloxyanisole --> 2-methoxy,5-hydroxy-allylbenzene
The above residue is refluxed for 3-4 hours to facilitate the claisen rearrangement. It is then cooled and basified with NaOH, and washed thrice with DCM. The aqueaous phase is then acidified, and extracted thrice more with DCM. The pooled 2nd stae DCM is evaporated and the crude product used directly.

Performing the Claisen rearrangement at reflux only gives crap. You need to use an oil bath and heat slowly. Once the reaction temperature reaches 200°C you need to stop heating since the rearrangement is exothermic. Once at 200-210°C the temperature will suddenly rise by itself even up to 250°C (depends on the reaction volume and your oil bath control). After 1h at 240°C the rearrangement is more or less quantitative.
Quote:
Let's just say that if anyone found this post thought provoking, it may be beneficial to read up on Ritters work in 1948 (JACS, i believe) on the preparation of secondary acetamides from olefins and acetonitrile.

Ritters' work clearly demonstrated that his reaction gives the corsponding dihyidroisoquinolines if used on allylbenzenes with the ring substituted with activating groups like MeO. The Ritter reaction only gives acetamides from allylaromatics where the aromatic ring is benzene or less nucleophilic than benzene. Read his work again.
Quote:
What's more, the acetonitrile could be prepared from acetic acid and urea, or acetic acid and ammonia, or from one of any number of ways that proceed to acetamide. There's a thread somewhere on this board that deals with the production of acetonitrile from acetamide and acetic acid (very simple, think mix+distill).

Acetonitrile is a ridiculously cheap solvent and no chemical suplier would have any problem selling it to you.

garage chemist - 15-4-2007 at 00:56

Already your first step will give dark brown crap instead of your desired product. P-aminophenol is unstable in alkaline solution, being oxidised to a quinone of sorts, so much that you will not be able to isolate any product.
You cant remove the acetyl group from paracetamol that easy!

Intergalactic_Captain - 15-4-2007 at 11:25

I realize that going to p-aminophenol first would be a mistake...I didn't have my thouhts completely together when I set this up. I chose not to use hydroquinone or p-aminophenol as these are not things you would normally find in the painkiller aisle at the supermarket...As for methylating agents, my basic choices are MeBr(not a liquid), MeI(not gonna buy iodides), Me2SO4(insidious carcinogen) - methyl nitrate is just easier for me to make/work with...

As for the acetonitrile part, I'm not sure why I even included that in this thread...I was doing a little more looking around last night and it appears that that particular reaction only works for allylbenzenes and non-phenolic analogues....The orgininal two articles by ritter never said this too clearly, and I figured I'd give it a shot...

Oh, and you go and try to buy what you want from a chemical supplier without a university/business/fistfull of cash behind you. First off, not only is it damn near impossible to do so, It is also about as far from economical as possible to place small orders.

This is the MSDB. The last I checked, the spirit of this site was the promotion of amateur science. A garage chemist (not referring to the member, though he illustrates my point) does not go through his VWR catalog to plan his syntheses...He takes $50 to wal-mart and spends the rest at the hardware store. The only thing we're accomplishing by starting with substrates closer to our products is giving up the spirit that makes us who we are...All right, maybe I'm one of the last people that should be saying this, but I'm sure you all get the point.

No, I'm not starting from p-methoxyphenol. Nor am I starting from hydroquinone. I'm not buying acetonitrile (though I guess I don't need it anyway...yet). I'm not even going to open a chemical catalog. I am going to use a rediculously overcomplicated process for the production of something that I'm not sure I'll even find a practical use for when I'm done.

And Nicodem, I do appreciate your input. Along with everyone else here...Keep it coming if you can. So, now that that's out of the way, heres the new idea...

tylenol -> methoxyparacetamol(no idea on the name) -> p-aminoanisole -> p-metoxyphenol -> p-allyloxyanisole -> 2-methoxy,5-hydroxy-allylbenzene -> 2,5-dimethoxyallylbenzene

Baiscally the same, same reagents, same procedures, except for the claisen rearrangement (which I admittedly have little information on thus far anyway)...That and the hydrolysis step, I've got to dig up a little more but I know that it's at least 90% and very simple conditions.

Oh, and solvents...I figured someone would get me on that...DCM is one one of those chemicals that would be recycled to the last drop...And look at the order I laid them out in...The order of switching from toluene to DCM is based on not having to pour anything back into the funnel except fresh solvents/washes.

I'm sure I missed something here, but I'm off to have a smoke and go to the library. Once again, if anyone has any input, I'll gladly take it...Just don't tell me something can't/shouldn't be done without an explanation.

solo - 16-4-2007 at 08:59

It's interesting to see the revival of this starting material since ning (acetaminophanatic) had so many similar ideas about this material.....I wonder?......solo

Intergalactic_Captain - 16-4-2007 at 12:34

Actually, I have been thinking about this for quite a while...I was going to post this when he posted the benzoquinone thread, but I figured I'd see how that one went...It appears to have disappeared to the sands of time now...

Hopefully, someone out there figures out something worthwile to make with paracetamol...It's kind of like cigarettes and beer - Although there are probably rooms full of evidence that this drug is more harmful than it's worth, it'll never leave store shelves.

Nicodem - 16-4-2007 at 23:37

Quote:
Oh, and you go and try to buy what you want from a chemical supplier without a university/business/fistfull of cash behind you. First off, not only is it damn near impossible to do so, It is also about as far from economical as possible to place small orders.

Have you even tried? I never had any problems placing an order as a private person unaffiliated with any business or institution. Unless you order some regulated chemicals requiring filling of forms, they don't give a damn about any affiliation (except for paying arrangements). Though I guess this is different and depends on the country and reseller you deal with, yours is more likely just a prejudice.

Anyway, here are the references for the O-methylation of acetaminophen (I hope you read Chinese):
Quote:
Originally posted by solo
It's interesting to see the revival of this starting material since ning (acetaminophanatic) had so many similar ideas about this material.....I wonder?......solo

Yes, it brought the same memory to me as well. I wander where that wonder kid is now? He would spend days in the library searching through SciFinder to provide the references for the whole synthesis.

Intergalactic_Captain - 17-4-2007 at 09:45

Thanks, I guess, though I can't read chinese...I think I will look a little further into dimethyl oxalate, however. I did a quick bit of searching around for both dimethyl carbonate and oxalate, and have found that in a small laboratory setting, preparation the oxalate seems preferable. I found a couple articles regarding its production from (all reagents anhydrous) methanol and oxalic acid via HCl catalysis if anyone's interested - For some reason I've been having trouble downloading JACS pdf's recently, so all I've got for them are the DOI's - ja01361a034 and ja02237a015. Both articles are pretty old and one of them has no mention of yeild, but they are given as practical procedures for the preparation of dialkyl dicarboxylic acids, so I'm assuming the yeild is at least moderate.

What I have yet to find, though, is any information on the use of dimethyl oxalate in a methylation reaction. What little I have indicates that Acetone/Na2CO3 may serve as a reaction mixture, though I cannot access the actual article - only the beilstein description. Unfortunately, my university library doesn't have the article (and I can't read german too well anyway). I'm heading back there in a couple hours, though, so I might find something yet.

Is dimethyl oxalate a newer reagent, or is it just not used that often? I was able to find hundreds of articles on JACS on dimethyl carbonate, but very few and none of relevance when I tried the oxalate. Tetrahedron Letters gave me three irrelevant articles...I know I should be searching more, but I don't really have the attention span to photocopy and hand-translate foreign languages, especially the germanic ones.

Reference Information

solo - 17-4-2007 at 12:43

THE PREPARATION OF PHENYLETHYLBARBITURIC ACID
MARY RISING AND JULIUS STIRGLITZ
J. Am. Chem. Soc. vol.40, Pg. 723, 1918

Abstract
Phenylethylbarbituric acid is a member of the ureid group of hypnotic
drugs, of which diethylbarbituric acid, introduced as “veronal” and now
known as “barbital,” is the best known and most important representative.
Phenylethylbarbituric acid, “phenylbarbital,” introduced as “luminal,’)

Attachment: THE PREPARATION OF PHENYLETHYLBARBITURIC ACID-ja02237a015.pdf (549kB)
This file has been downloaded 891 times

Reference Information

solo - 17-4-2007 at 12:50

ALKYL OXALATES AND OXAMATES
PETERP . T. SAHA ND SHIH-LIANGC HIEN
J. Am. Chem. Soc. vol.53, pg.3901, 1931

Summary
1, A simple, general procedure for the esterification of a di-basic acid
2, The simple physical constants of five dialkyl oxalates are reported.
3. By the action of the calculated amount of ammonia on the dialkyl
oxalates, six alkyl oxamates were isolated. Among these, the isopropyl
and n-butyl esters are new compounds. The methyl, n-propyl, and isobutyl
derivatives have been mentioned previously, but their melting points
are for the first time accurately given.

Attachment: ALKYL OXALATES AND OXAMATES.pdf (194kB)
This file has been downloaded 765 times

Nicodem - 18-4-2007 at 00:05

Dimethyl oxalate preparation: http://www.orgsyn.org/orgsyn/prep.asp?prep=cv2p0414
Quote:
Originally posted by Intergalactic_Captain
Thanks, I guess, though I can't read chinese...

Too bad, because the reference for the Sandmeyer reaction for p-methoxyaniline to p-methoxyphenol is also in Chinese:
Xiangtan Daxue Ziran Kexue Xuebao, 22(2) (2000) 54-56. (1. NaNO2/H2SO4/H2O; 2. Cu(NO3)2/CuO/H2O; 85% yield)
Quote:
What I have yet to find, though, is any information on the use of dimethyl oxalate in a methylation reaction. What little I have indicates that Acetone/Na2CO3 may serve as a reaction mixture, though I cannot access the actual article - only the beilstein description.

I'm only familiar with diethyl oxalate for alkylations, which requires drastic conditions, but I seriously doubt that dimethyl oxalate would be so much more reactive as to allow such extremely mild conditions as Na2CO3/acetone which don't even work for alkyl bromides (you need at least K2CO3 and still it does not always work). Anyway, if you need to prepare dimethyl oxalate then I see no advantage over using MeBr instead. Prepare a solution of MeBr in ethanol and use it for methylating your acetaminophen with KOH in ethanol. Way simpler and gives better yields than any method with methyl oxalate.
Quote:
Unfortunately, my university library doesn't have the article (and I can't read german too well anyway). I'm heading back there in a couple hours, though, so I might find something yet.

You speak English, a Germanic language, so you should be able to understand enough, especially if you help yourself by using machine translation. Anyway, give that reference, I really want to see a claim of alkylation with an oxalate in Na2CO3/acetone!
Quote:
Is dimethyl oxalate a newer reagent, or is it just not used that often?

No, it just don't make any sense to use it when dimethyl sulfate is so ridiculously cheap, full proof, general and works on all phenols, not just some small, heat and base resistant ones like dimethyl oxalate does. You don't see anybody using methyl nitrate either, don't you? The reason is similar in addition to explosion risks. The reason why you see so many references for dimethyl carbonate is due to the recent hip about the "green chemistry" crap. It is a matter of fashion (yes, most chemists are much worse than women in regard to fashion).

[Edited on by Nicodem]

Intergalactic_Captain - 18-4-2007 at 08:08

Machine translations suck ass...And just cause I speak english doesn't mean that I would be any better at germanic languages than someone who doesn't - Trust me, I've spent more time than I care to have wasted trying to learn spanish, german, and japanese - They just won't stick. Aside from the very basic rudiments of sentence structure, I really lack the skillset/attention span necessary to do anything productive with a foreign language.

And as for dimethyl oxalate, I think I'll give it a shot anyway. It'll either work or it won't, and if it doesn't, there's a couple other esoteric uses for it. And I see where your (Nicodem) argument is coming from towards using more standard methylating agents - But, I don't think you see where mine comes from...This is the last time I'll bring it up, but take methyl nitrtate for example - Any experienced chemist would call someone a reckless dumbass for considering it as a methylating agent, despite the fact that it does work rather effectively. The risk of explosion, rising exponentially with the size of the batch, simply outweighs the benefits of its relatively simple preparation and extraction - IE, it is very simple to make with drain cleaner, an instant cold pack, and some methanol - No fancy reagents, no fancy glassware, just mix up the acid and nitrate, cool, and stir in the methanol.

As for MeBr, I have been putting some thought into its use. My main problem, however, is that I do not have the best venting and performing the reaction outside would detract from the stability of my setup. Secondarily, I would not make it as used - I would prepare a moderately large (on a lab scale) batch, and store it between uses. Unfortunately, my chemical storage is directly under the paper-thin, uninsulated living-room floor of my 200 year old house...IF there was even the slightest leak in whatever container I was using to store it, I'd be basically sentencing my family to early, cancerous deaths. Maybe that's a little drastic, but you get the point. The basic idea is the same with DMS - I could make it easily enough, I suppose, but regarding it's synthesis I would prefer to do a larger batch rather than smaller ones, leaving the remainder in storage while I am at school.

Looking at which reagents to use, my decisions are not based on matters of convenience - Rather, they are based on choosing the ones that are less inconvenient. I've got a lot of choices in mehtylating agents, each with its own strengths and weaknesses. Unfortunately, all of them (the most used ones, at least) are insidiously poisonous. Combine this with an improper lab from the start, and you can see where my problems come from. Don't get me wrong, I would love to use MeBr just for it's sheer simplicity - Unfortunately, my situation dictates its designation as nothing more than a final option when all others fail.

Ullmann - 24-6-2007 at 14:04

It is a very long route to a not so useful substrate IMHO. You would do best to search another way to achieve the synthesis of the final compound you have in mind... At least you should really listen to nicodem and make p-meo-phenol from hydroquinone then proceed as on rhodium. Source hydroquinone it will be more useful chemical.

Acetaminophen is a waste of time as a precursor IMHO but maybe as a source to benzoquinone as ning suggested. There was a three steps route from benzoquinone to the allyl-DMB using silver persulfate on the old hive.

For your methylation issues, why don't you make some methyl-tosylate from tosic acid and trimethyl borate (borax + acid + meoh then distillation) and use this as a DMS substitute?

jon - 6-7-2007 at 10:05

why not start with anethole (p-methoxypropenyl benzene) oxidize this with bichromate and convert this to methoxy-phenol. If you just want something tedious to do.