Route to 2C-B?

[fogged]

Let's imagine someone wanted to take a shot at making some 2C-B.  What would the bees think of the following route to such a compound?

1 - Hydroquinone --> p-methoxyphenol
   Hydroquinone in methanol with benzoquinone and concentrated sulfuric acid according to Antoncho in

Post 269667

(Antoncho: "Re: P-MeO-phenol from hydroquinone: part II", Novel Discourse).

2 - p-methoxyphenol --> 2-hydroxy-5-methoxybenzaldehyde
   Reimer-Tiemann reaction (p-methoxyphenol in NaOH solution and CHCl₃ added) according to the article posted by Rhodium in

Post 475637

(Rhodium: "Synthesis of 2C-B from Anise Oil (Anethole)", Novel Discourse) and the procedure in Karl's post

Post 214710

(Karl: "2-Hydroxy-5-methoxybenzaldehyde", Chemistry Discourse).

3 - 2-hydroxy-5-methoxybenzaldehyde --> 2,5-dimethoxybenzaldehyde
   Methylation with DMS (made using the method for diethyl sulfate given on Rhodium's page at

https://www.thevespiary.org/rhodium/Rhodium/chemistry/diethylsulfate.html

, substituting MeOH for EtOH, of course) according to the paper in Rhodium's post

Post 475637

(Rhodium: "Synthesis of 2C-B from Anise Oil (Anethole)", Novel Discourse).

4 - 2,5-dimethoxybenzaldehyde --> 2,5-dimethoxynitrostyrene
   React 2,5-dimethoxybenzaldehyde with nitromethane according to, once again, the paper posted by Rhodium in

Post 475637

(Rhodium: "Synthesis of 2C-B from Anise Oil (Anethole)", Novel Discourse).  Or perhaps following Barium's work, using methylamine in MeOH as a catalyst, as in the post

Post 419399

(Barium: "High-yielding nitrostyrene catalyst", Methods Discourse)

5 - 2,5-dimethoxynitrostyrene --> 2C-H
   Reduce the nitrostyrene using an Al/Hg amalgum, according to Sunlight's work in

Post 108517 (missing)

(dormouse: "A 2C-B story. Cold cooking  -sunlight", Novel Discourse) and the info on Rhodium's page, at

https://www.thevespiary.org/rhodium/Rhodium/chemistry/znhg.alhg.reductions.txt

(Yes, I know better yeilds are potentially achievable using other reductions, but this seems like the best compromise between yeild, ease, availability and reliability).

6 - 2C-H --> 2C-B
   Bromination with Br₂ in glacial acetic acid as seen in so many posts and on Rhodium's page.


Well, anyone want to offer any support, criticism, alterations or hints?  Thanks people  

[Rhodium]

Yes, that's a very good idea, but maybe you should also look into

The Leminger Nitrostyrene Reduction

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/leminger.html)

[Vitus_Verdegast]

3 - 2-hydroxy-5-methoxybenzaldehyde --> 2,5-dimethoxybenzaldehyde
Methylation with DMS (made using the method for diethyl sulfate given on Rhodium's page at

https://www.thevespiary.org/rhodium/Rhodium/chemistry/diethylsulfate.html

, substituting MeOH for EtOH, of course)

As you probably know dimethyl sulfate is very toxic and carcinogenic, so making it yourself is not without risks. Due to its toxicity the access to the commercial product is also more restricted. A good alternative, less toxic and easily obtainable would trimethyl phosphate.

https://www.thevespiary.org/rhodium/Rhodium/chemistry/me3po4.html

Post 415141

(Bandil: "Preparation of 2,5-dimethoxytoluene via TMP", Novel Discourse)

Post 415780

(LiquidGaia: "Syringaldehyde  How watched is this??", Chemicals & Equipment)

Post 261892 (missing)

(uemura: "Re: trimethyl phosphate", Chemistry Discourse)

Post 265013 (missing)

(uemura: "Methylation with (CH3)3PO4", Chemistry Discourse)

[moo]

I recall some bee having problems with the purification of p-methoxyphenol using that route due to certain byproducts. In 

Post 421068

(Mountain_Girl: "P-MeO Phenol abstracts 1980-1999 #1", Methods Discourse) you can find a reference to

Patent DE3145212

aka

Patent US4469897

which details producing p-methoxyphenol from hydroquinone using MeOH, catalytic CuCl₂ and O₂ or air. Most of the examples are run under pressure but there is one example that shows it can be done under reflux. I assume this method would be a bit cleaner but have no empirical evidence. I'm sure many bees here would appreciate such information.

If you are going for the Al/Hg, it might be possible to get better yields, see

Post 474331

(moo: "Generalization?", Serious Chemistry).

[dioulasso]

1.    The R-T formylation of p-MeO-phenol (unpurified, from monomethylation ala Antoncho) does not give the desired 70%+ yields. This according to both Antoncho’s and own experiences.
This reaction is quite sticky (much tar) and the workup is lengthy   , but goes smoothly .


2.    A good alternative to the R-T formylation would be the Mg(MeO)2 formylations described in:

Post 290438

(Lilienthal: "2-hydroxy-5-MeO-BA: The easy way", Chemistry Discourse)
and

Patent EP0529870

These formylations are supposed to give 90%+ yields !

A recently described run by DTT gave 80% yields , which is better than the best expectable yields from R-T formylation !      

Post 472860 (missing)

(DDT: "Ôîðìèëèðîâàíèå...", Russian HyperLab)

It is likely though that this reaction would run much worse (if at all) on the crude home made p-MeO phenol   .


AnyBees have further experiences w/ the monomethylation and/or R-T formylation ?

[Rhodium]

Could we have that post translated to english, please?

[Antibody2]

the cold condensation on rhodiums page using NaOH catalyst is higher yeilding (ca 95% on DMBA) and avoids the need for methylamine or reflux.

[fogged]

Hey, thanks for the responses... Rhodium, you're a legend - a response within 9 minutes!!

Anyway, Rhodium, I did see the Zn/HCl reduction posts (and am aware of the principle anyway) but none of the posts I found seemed to indicate it was a consistent reaction... I did, however, miss the page you linked to, and so will look into it further.  That article, as well as the posts I subsequently found from GC_MS looked promising, I'll have to say.

Vitus, thanks, I am well aware of the dark side of DMS... however, as I understand it, the main reason TMP is "safer" than DMS is because of the lower volatility.  Taking reasonable precautions (an improvised but decent fume hood and protective gear), DMS should be reasonably safe (as safe as a powerful, reasonably volatile carcinogen can be, that is).  Combine that with the fact that TMP isn't as easy to make, nor as OTC, and it makes DMS look like the best option.  Thought was given to using MeI, but this was discarded as well.

moo, thanks muchly, will look into it... at first glance, though, it seems a little ugly to perform, but it might be worth it...  And as far as the Al/Hg, well, yeild isn't amazingly important (we'll assume reasonable access to precursor and interest only for personal research   ).  Iwill take the points in that thread into account, though.

dioulasso, I knew about the relatively low yeilds and tedious work up for the R-T formylation... the apparent reliability of the process was a big turn on, however!  And, once again, yeild isn't a huge factor.  However, if some magnesium can be found, it could very well be worth a try.

Finally, Ab2, thanks for the pointer... sounds easier and definitely more simple reagents! I really can't believe I missed that one... excuse me while I go kick myself  

Thanks for the responses people, most helpful!  If there's anything else, please comment.  The more input the better!

[fogged]

The first experiments with hydroquinone only got as far as the formylation stage where a number of factors conspired to prevent anything else being done.

Hydroquinone --> p-Methoxyphenol
  - Weighed ~1g dry benzoquinone and 10g hydroquinone into 250mL FBF.
  - Added 55mL MeOH and 11mL H₂SO₄ (acid stupidly added quickly to MeOH, causing some to boil off, so an extra couple mL's MeOH added to make up.  Also plunged into ice bath to cool it down to RT).
  - Stirred at RT for ~24hrs
  - Mixed with 100mL NaCl solution, then extracted with 50+30mL Xylene.
  - Xylene mostly distilled off (forgot to neutralize here... stupid!! Added a little xylene, did the NaHCO₃ swirl, filtered and redistilled)
  - Gently heated in a beaker to remove remaining xylene.  The beaker was left on the hotplate to cool (the stirrer remained on) overnight. The next morning, there was a snazzy crop of crystals on the bottom of the beaker!  Dark brown, perhaps a slight red-ish tinge, but definitely crystals!).
  - Weighed while still smelling slightly of xylene - 6.30g of (presumably) p-MeO-Phenol - 64.3% based on hydroquinone - not too bad!.  

This yeild was somewhat less than Antoncho's, which can probably be explained partly by some sloppy chemistry and lack of following directions, but more likely because of sublimation (a repeat batch was heated a little too much at the xylene-removal stage, resulting in a large crop of brilliant white, needle-like crystals at the top of the beaker). This reasserts Antoncho's reccomendation to use a lower boiling solvent than his original toluene, however xylene was chosen so as to screw with the procedure as little as possible, being the closest thing to benzene or toluene available. Would DCM be a possible choice for future experiments?


The formylation was then attempted:
  - 6.3g p-MeO-phenol was placed in a 100mL RBF with 16g NaOH in 18mL H₂O.
  - Flask was fitted with a condenser, flushed with butane and magnetically stirred in a water bath at 65-70*C (temperature did not leave this range the entire time, and was almost always at 70).
  - Over three hours, ~8mL of chloroform was added through the condenser, about 1mL every half hour (this seemed like the best course of action, as all the procedures, from Antoncho's with 12g to Karl's and the other paper I followed so closely with >100g taking 3 hours for addition).
  - After addition was finished the reaction was left to go for another hour.
  - Acidified with ~50mL of 25% H₂SO₄, and the expected oil layer formed on top.
  - Extracted with DCM, swirled with NaHCO₃ and the solvent removed.

This left perhaps 3-4mL of black oil in the flask, approximately what was anticipated.  A sample of maybe .25mL was shaken with a saturated sodium bisulfite solution. It seemed to change fairly quickly from an oil that happily floated on the water to a black tar-like substance that stuck quite happily to the sides and lid of the vial - is this a positive result?  Steam distillation was planned, but due to a range of interruptions it never happened. The oil was placed in a flask, flushed with butane, tightly stoppered and put in the freezer. If that doesn't protect it, nothing will.  It might get pulled out and played with some time in the future!


Also, regarding the DMS synth (which was also attempted) - procedure from Rhodium's site was followed more or less exactly (with the same molar amounts of reagents, changed from EtOH to MeOH, of course), oil bath at ~150*C, using a pump that should have pulled DMS over at around 120-130*C.  However at some point it became obvious that a whole bunch of stuff wasn't coming over, but was collecting in the boiling flask and trying to bubble over and carry sodium sulfate goop into the condenser... in the end, about 4mL of (presumably) DMS was collected (formed a layer below distilled MeOH, was about the right density, and when the receiving flask was left for maybe a day, the tiny little bit of bottom layer that the pippette couldn't get had dissapeared, presumably hydrolysed - apart from BP, are there any other simple tests for DMS?).  Anyone with suggestions as to what went wrong (because this is gonna have to be attempted again   )?  In hindsight, the stuff in the boiling flask was probably mostly DMS, considering that any H₂SO₄ should be mopped up by the sodium sulfate...

[Vitus_Verdegast]

Anyone with suggestions as to what went wrong (because this is gonna have to be attempted again )?  In hindsight, the stuff in the boiling flask was probably mostly DMS, considering that any H2SO4 should be mopped up by the sodium sulfate...

oil bath at ~150*C, using a pump that should have pulled DMS over at around 120-130*C.  However at some point it became obvious that a whole bunch of stuff wasn't coming over, but was collecting in the boiling flask and trying to bubble over and carry sodium sulfate goop into the condenser

Am I right to assume that you heated the mixture of methanol, sulfuric acid and sodium sulfate to 150°C ? If so, then of course sodium sulfate will release its water, causing methyl hydrogen sulfate to hydrolyse   .

You are supposed to mix a molar excess of methanol with a mol of H2SO4, add anhydrous Na2SO4, and after some time, allowing the Na2SO4 to absorb the water formed by the reaction  MeOH + H2SO4 <^__> MeHSO4 + H2O, decant the mixture (now 90+ % MeHSO4) into the flask and start vac distilling.

If I was you I'd still prefer trimethyl phosphate. It is not at all hard to make (P2O5 and methanol) and in much safer conditions IMHO.

Post 265013 (missing)

(uemura: "Methylation with (CH3)3PO4", Chemistry Discourse)

[fogged]

Hi Vitus, thanks for the reply...

Reading the diethyl sulfate procedure on Rhodium's site (which is what was essentially followed for making DMS), it seems (to me, at least) that it says to drip the MeOH/H2SO4 mix onto NaSO4 held at 150*C and distil from there.  However the method you mention does seem to make more sense... have to try it next time.

Also, regarding TMP, is it as strong a methylating agent as DMS?  is there a procedure anywhere for methylation of 2-OH-5-MeO-BA (I couldn't find anything in TFSE)?  If not, how many methyl groups can TMP add (ie. 1, 2 or 3)?  The main reason (other than lack of specific procedures) that DMS was chosen is that P2O5 is a little more difficult to come by... otherwise it would have at least been tried!!

[Vitus_Verdegast]

Look, try this: Place some Na₂SO₄.10H₂O in a beaker, put the beaker on the hotplate and heat slowly. Around 33°C it will melt and the anhydrous salt will crystallize out. Another thing, how can sodium sulfate bind water at 150°C, if water boils at 100°C ? You will probably also boil away (part of) your methanol then (bp 65°C) so your reasoning holds no logic.

It is very simple, look:

CH₃OH + H₂SO₄ <--> CH₃HSO₄ + H₂O


and at room temperature: Na₂SO₄ + 10H₂O ^__> Na₂SO₄.10H₂O

Simply if you don't have any water molecules available anymore, the equilibrium will be shifted to the right and your product will be methylhydrogen sulfate. Then, decant this off the now hydrated sodium sulfate and vacuum distill, using the necessary precautions considering the extreme carcinogenicity and toxicity of dimethyl sulfate.

All this information was taken from a basic chemistry book, and you can find all this with google too.

It is only about learning how and where to search.

I recommend you to read up alot more about what you are doing, what is happening and why. You need to understand everything perfectly about each step, especially if you want to prepare very noxious compounds. It'll make your endeavours much less frustrating   .

Trimethyl phosphate is a far better choice, not only because the toxicity is less (but remember all alkylating agents are carcinogenic), but it can substitute for DMS in many occasions. I'm pretty sure it will methylate 2-OH-5-MeO-BA, it methylates vanillin (3-MeO-4-OH-BA, so both are homologs) without much problems. UTFSE for it, I remember there is a patent somewhere on that.

TMP will have 1 methyl available, as Na/K dimethyl phosphate will only be a poor alkylating agent, similar to Na/K methyl sulfate. So that is pretty similar to DMS, which also gives 1 methyl off easily, while the other is much more difficult and requires elevated temperature.

Don't worry about ordering a moderate amount of P₂O₅, as it is a commonly used drying agent. Not watched at all (at least in Europe, don't know about the USA).

[fogged]

Hi Vitus, sorry if it seemed like I wasn't listening to or was arguing with you, that was me sort of thinking out loud!  Everything you said makes perfect sense, and I agree totally.  I do fully understand what's going on in the reaction, and the point of everything in there, it's just that I would never have thought of the sodium sulfate releasing any complexed water at those temperatures (even though it seems fairly obvious that this is exactly what would happen!).

Thanks for the pointers about TMP - again, what I would have expected, but it's nice to get confirmation.  May have to have a look around, see what I can find in the way of P2O5 (I mean, even if it isn't used for TMP, there are plenty of other jobs for it!).

Once again, thanks for your help!

[Ruthenium]

Ninety grams of sodium sulfate is placed in a dry 1 liter flask connected with a condenser and a receiver arranged for vacuum distillation. The flask is heated by means of an oil bath to 155-165°C. The apparatus is exhausted as nearly as possible by means of a filter pump, and misture of 50 grams of ethanol and 104.5 grams of concentrated sulfuric acid is allowed to drop through a capillary tube on the sodium sulfate at a rate of 120-150 drops per minute. The distillation of the mixture requires about one and one half hours for completion. The distillate, which consists of ethanol and diethyl sulfate is poured into a separatory funnel, the ethanol may be recovered for further use. The diethyl sulfate is washed with a dilute solution of sodium carbonate and then several times with cold water, then dried with anhydrous sodium sulfate, yielding 32.4 grams.

Reference: JACS 46, 999-1001 (1924)

I see absolutely no mention to a room temp reaction followed by decantation and subsequent distillation. I am not arguing with you vitus, but this method does not mention these details.

I now know where my synths also failed. How long does the methanol and H2SO4 need to sit over the sodium sulfate and at what temp before distillation?

[dioulasso]

For the prepn of Methyl hydrogensulfate see the belo posts by Antoncho :

Post 256342

(Antoncho: "Methylation of hydroquinone w/NaMeSO4: good news!", Novel Discourse)

Post 233762 (missing)

(Antoncho: "Kitchen nitroalkane success!", Chemistry Discourse)

I would imagine that by distilling the thus obtained MeHSO4 under vacuum, one can obtain good yields of Me2SO4. Though I have only used MeHSO4 for NaMeSO4 methylations...

And carefull w/ the Me2SO4 destillation!
Especially when cleaning the apparatus after use. Flush everithing w/ conc. alkali solution.

[moo]

Doing things the way that seems most effective can prove to be a bit too effective. Concentrated ammonia can react with dimethyl sulfate with explosive violence, so use dilute ammonia. See

http://www.dupont.com/dms/properties/chemical.html

.

[fogged]

Well, with some time over the recent long weekend, a repeat of the R-T formylation as outlined above was given a go with some leftover p-MeO-phenol.  Slightly less phenol (5.5g, with the other quantities likewise scaled down) was used, as was a recently acquired addition funnel, so the chloroform was added probably over an hour or so.

The reaction was consistently maintained at 65-70*C, and was reasonably well stirred the whole time (anyone who's tried this knows about the tar problems!).  Managed to forget to flush the damn system with butane, too - remembered as the flask was being removed from the clamp!  Anyway, it was left heating and stirring for about an hour and a half after the chloroform was all added, then it was acidified with H₂SO₄ (took quite a bit, actually - more than expected from the writeups I've read).  After that, an attempt was made to extract the mix with DCM, but the layers were impossible to distinguish, so that was given up and the whole mess was thrown into a larger flask and steam distilled.  Collected about 600mL of distillate, then saturated with NaCl, before extracting with DCM (small sep. funnel led to 3x200mL batches, each extracted with 50+30+10mL DCM).  The water and crud remaining in the distillation flask were still quite orange-red - I assume mostly random impurities.

The DCM was then swirled with anhydrous Na₂CO₃ (to both neutralize and dry it), then distilled off, to leave around a mL of light orange-ish oil (0.85g).  It was then put into a vial and stored under butane.  It remains liquid at room temp, but forms crystals in the fridge - it sort of formed plates at the bottom, but there was some on the sides that were more like needles.

An IR showed that it was definitely 2-OH-5-MeO-Benzaldehyde, and it seemed reasonably clean (fairly sharp fingerprint region, and all the significant peaks could be assigned). 

I was pretty damn pleased with all this!  12% yield isnt horrible from what I've read (particularly since most people say it's a reaction that you need to do a few times to get it right).

One question for anyone who's game - assuming it remains under inert gas and in the fridge, how likely is this beast to oxidize or otherwise decompose?  Because it'd be pretty annoying to end up trying to condense the acid with nitromethane... and in my experience, broken chunks of molecules don't react that well, either!!

[karl]

12% is a terrible yield for this phenol, The reaction is very straight forward excellent results were obtained on my first attempt which was why I was so impressed with it. I did note that after acidification, the water which was black and thick with solids, became a nearly clear yellow which allowed for seperation. I didn't like the idea steam distilling the oil with excess H2SO4 in the solution at the time. The remaining water after the steam distillation was distinctly red however.

I don't think the reaction was run for long enough or on too small of a scale.

The longest I kept some in a freezer, no inert atmosphere, was for about 8 months and no decomposition was evident.

[amine]

why the benzaldahyde route?
I know that most bees take this route, mainly IMO because it is established, aldahyde ---> nitrostryene ---> amine. but have u considered taking one of the routes outlined in the novel discourse, specifically the methyl bromination of 1,4-dimethoxybenzene, followed by SN2 attack via NaCN to make the cyanide intermediate, then reduction of that triple   carbon nitrogren. Swim has no experience with NaCN. If precautions are taken I'm sure it will be ok,  the only issue swim has is disposal of the excess -CN.

But there are less steps in the rxn, so total yields will be higher.

[_mu_]

But there are less steps in the rxn, so total yields will be higher.


You sure?

fictive route a):two 80% steps. Yield: 0.8*0.8 = 64 %

fictive route b):three 90% steps. Yield: 0.9*0.9*0.8=73%.