Hello,
I wanted to make a thread where methylations using trimethyl phosphate (TMP) can be discussed. It is often thought of as a safer, "greener" methylating agent, and has been used to methylate phenols and phenolic aldehydes in dimethylformamide or solventless. I'm sure all those interested in this topic have seen the same repeated examples of TMP's usage. I will give some examples of how I have utilized it, and would like to see some other peoples attempts, whatever it may be, using this reagent. Hopefully we can get some experimentation going on, because i think it has a lot of potential.

While TMP is generally regarded as less dangerous than other alkylating agents precautions should always be taken. If you don't have a fume hood, then do all transfers of reagent to the syringe/addition funnel etc outside, wearing gloves. It's always better to be safe, right? 

On to the fun stuff, here are a few of my examples, I will add more later.

Methylation of Hydroquinone to 1,4-dimethoxybenzene

This was based off the vague example I had seen in a rhodium page, I've tried this on a few different scales but the max yield I could obtain was around 75-80%. This is not too bad though.

Potassium hydroxide flakes (12.3g, 220mmol, 2.2 eq) were dissolved in dH2O 60ml. Caution, it gets quite hot. This still hot solution was added to a 250ml RBF containing a stir bar and a vacuum was pulled while stirring to try to remove as much dissolved oxygen as possible. This can be skipped, I only did it because I could.
The flask was filled with butane and Hydroquinone (11g, 100mmol) was added quickly, attaching a condenser to the flask after addition.
 Solution is stirred and flask heated to around 60 degrees C. A dark yellow/brown solution is obtained. To the reaction mixture is added trimethyl phosphate (32.2g, 230mmol, 2.3eq.) via syringe in one portion. After addition, the flask is heated with stirring in a boiling waterbath for 1hr 30mins.
Molten 1,4-dimethoxybenzene can be seen in the flask, along with some crystallization from sublimated product in the condenser.
The flask is cooled and the product crystalizes from solution. Workup can be done 3 ways:
1. Filter the crude product, triturate with 5% aq NaOH and recrystallization.
2. Extracted into DCM or other suitable solvent, washed with dilute NaOH, water, drying and evaporation.
3. Steam distilled.
I only filtered, but steam distillation should work very well.
So, after filtering and triturating with NaOH to remove any HQ or 4-methoxyphenol, crude brown crystals of 1,4-dimethoxybenzene are obtained, filling the room with their glorious scent. Yield 10.6g, 76.7%.

The crystals are brown, but pure enough for most further reactions. However it's always good to recrystallize to get your white crystals. Another option is steam distilling but if you were planning on doing that, you would have done it at the end of the reaction in the first place.

Methylation of 2-hydroxy-5-methoxybenzaldehyde

Now, this example uses DMF but I said somewhere else on this board that this aldehyde is best methylated as it's potassium salt, solvent less. I do not have notes on when I did it, and so right now I will not write any more about it. When I repeat it, I will give more details. But it works a bit better than this. Anyway:

2-hydroxy-5-methoxybenzaldehyde (5.2g, 34.2mmol) was dissolved in dimethylformamide 50ml. Powdered anhydrous potassium carbonate (7g, ~1.5eq 50.6mmol) was added to the solution and it was stirred for 20 minutes at RT with protection from atmosphere. The solution turns bright orange, really beautiful. It is then brought to 50 degrees C internal temp, and trimethyl phosphate (8.6g, 61.5mmol, 1.8eq) was added in one portion. Internal temp was kept at 70-75 for 3 hours. The solution is brown.
It is cooled and poured into 200ml ice cold H2O, and stirred for about 15 mins. Precipitated crystals are filtered, triturated in 50ml dilute aq NaOH, then 200ml H2O.
After drying, 2.4g of light brown 2,5-dimethoxybenzaldehyde with no smell of 1,4-DMB are obtained. yield
42.1%

The phenolic aldehyde was obtained by Mg methoxide/paraformaldehyde formylation and distillation. If using the aldehyde without distillation bisulfite purification should be used because there is always some dimethoxybenzene in there after the reaction. (unreacted 4-MP from formylation gets methylated, also, your 2,5-DMBA will usually precipitate as a very dark oil, or black crystals)

Methylation of 5-bromovanillin

5-bromovanillin (5g, 21.6mmol) is dissolved in dry DMF 25ml. Powdered anhydrous potassium carbonate (5.5g, 23mmol) is added after flushing flask/setup with butane (I really need an argon cylinder!). Flask heated to internal temp of 50C. Color changes from greenish to greenish/brown, an interesting color.
TMP (3.5g, 25mmol) in DMF 15ml was added over 5 minutes via syringe.
The solution turns to a more greyish brown and the flask is heated to 90-95C for 3 hours. It is then cooled to RT and 100ml H2O is added. Reaction mixture transferred to sep funnel, use DCM to wash product from reaction flask to funnel. It is extracted 3x 35ml DCM, combined organic washed twice with 100ml H2O to remove DMF prior to washing with 100ml 5% aq NaOH. ( keep base washes separate from any washes containing DMF as it will start to smell strongly of dimethylamine)
Org layer washed once more 100ml H2O, dried briefly with K2CO3 just to clarify solution, filtered thru cotton plug and evaporated.
Obtained a light orange oil, 3-bromo-4,5-dimethoxybenzaldehyde. yield 3.1g, MW 245, 58.5%.

So TMP definitely does work, I have not included a solventless example, but we know it works in DMF and aq alkali. More to come soon, I have a lot of TMP to experiment with.
 

I wish I could add more to this discussion, but suffice it to say for now that this is very impressive stuff. What's the availability of TMP? Probably not as eyebrow-raising as other methylating agents, but still...

TMP is not very easily made and there has been discussion on the subject. For some it may just be easier to get it, or maybe their supplier just got some in stock and it's an opportune buy. I would definitely not say DMS is ridiculously easily made, methyl iodide certainly is though.
Also I found it interesting that MeI gives very poor or no results alkylating 2-hydroxy-5-methoxybenzaldehyde (I have tried plenty of times!!), but TMP can do it.
I will have more examples to come in just a while, and for the record the patent for alkylating vanillin melt phase really works as described with very high yield.

2-isopropylthio-1,4-dimethoxybenzene

Done one pot, first alkylation of sulfur, then hydroxys with TMP.

In a 250ml RBF with stirbar and condenser is added 2,5-dihydroxythiophenol (6.5g, 45.7mmol) followed by dry MeOH 75ml. The mixture is stirred until dissolution to give a yellow solution and then a vacuum pulled to remove oxygen. Flask is then purged w/butane and potassium hydroxide (85% flakes, ~46mmol, 2.2g) is added which after dissolution gives a greenish solution.
2-bromopropane (6g, 48.7mmol) is added in one portion via syringe and then it is refluxed for 2 hours. After cooling the reaction is filtered quickly and salts washed with 40ml MeOH. The filtrate is moved to another flask, and the MeOH is removed under vacuum.
There is then added to the residue 75ml H2O, KOH (4.4g, 2eq) and it is stirred for 5 minutes.
Trimethyl phosphate (14g, 100mmol) is added in one portion and the reaction refluxed for 1 hour.
Flask is then cooled and diluted with H2O ~100ml. It is transferred to sep funnel, flask rinsed with DCM and the reaction mixture extracted 3x 75ml DCM. Combined extracts washed twice with 100ml dilute NaOH (aq.), 4 times ~75ml H2O then dried on MgSO4.
After filtration the solvent is removed to give 5.4g of amber oil 2-isopropylthio-1,4-DMB (25.4mmol, 55.5%).

Thank you,

Yes, let me explain something, although kind of off topic. I have tried the Sulfuric Duff with this substrate, but without ammonium acetate addition(the improved method, read more about it at hyperlab it is in the PEA thread already in English).

Now, at the time I did not have EtOAc at hand, so I tried evaporating most of the AcOH and just adding water and stirring overnight (I was kindly given an example of it working this way for 5-ethoxy-2-methoxy-4-propylthiobenzene). This gave me a 5% yield of the correct benzaldehyde.
I am quite certain if I used EtOAc for the hydrolysis like the examples it would have succeeded, with the higher ~70% yields reported for other alkylthios.

Now, I formylated this benzene also prepared in the manner above with POCl3/DMF and it worked as it should. I plan to use the Duff again with EtOAc and I will report what happens. All in due time.

You will need to find the examples that are at Hyperlab, in the "notes on the synthesis of PEA" thread. It is posted by member miamiechin.
Forget the method at SM, there is no need for the acetate addition. Plus I have tried it so many times on many things and it never worked. When you find what I am talking about you will understand completely. 

just out of curiosity, are you making your 2,5-dihydroxythiophenol from benzoquinone?

I just read a paper where they use sodium thiosulfate.  Yields are lower (38%), but it might be a cheaper, although I don't know how expensive thiourea is?

2-Mercapto-1,4-dihydroxybenzene I. A solution of 43.2 g of benzoquinone in 150 ml of glacial acetic acid was heated to 40 50C, and then a solution of 150 g of Na2S2O3 in 200 g of water was gradually added, avoiding warming-up of the reaction mixture by more than 10C. After short stirring, the transparent and almost colorless solution was saturated with KCl to precipitate sodium S-(2,5-dihydroxyphenyl)thiosulfate. A solution of 2.6 g of this salt in 10 ml of water was mixed with 20 ml of concentrated HCl, and 5 g of zinc dust was gradually added; the reaction temperature was maintained at 40 50C until the gas evolution ceased.

edit: nevermind, thiourea is dirt cheap.

I'm waiting on more O2 to make myself some benzoquinone.  I've got a kg I bought a year or two ago but due to improper storage it has degraded severely.  I'll order some thiourea and report back.

Oerlikon: an O2 balloon on top of a flask of hydroquinone in DCM + 1 drop of HCl is pretty good, no?  Quantitative yield, no filtering out I2, etc.  It's very clean.  I just a rubber septum and a needle.  Piece of cake.