Ethyl diacetoacetate 12.50g (72.6 mmol) was added to a stirred slurry of caesium carbonate 50.5g (155mmol) in anhydrous acetonitrile (300mL) in a 1L flask. A white voluminous precipitate formed. The mixture was stirred for 30 min at RT, then cooled to 0C. Neat methyl triflate 9.5mL (86mmol, DANGER) was carefully added, dropwise over 10 min and the mixture was stirred under Ar on a melting ice bath (0 to 20C) for 1 hour, then at ambient temperature for 11 hours (overnight). The entire slurry was concentrated to a small volume on rotavap. Solid formamidinium acetate 31.2g (300mmol) was added to the residue followed by a solution of sodium ethoxide, made freshly by dissolving sodium metal 5.05g (220 mmol) in 0.5L of anhydrous non-denatured ethanol. The mixture was refluxed on oil bath under blanket of Ar for 4 hours. (Some ammonium carbonate sublimate deposited in the reflux condenser). The reaction mixture was cooled, filtered and the filtrates evaporated. The residue was portioned between dichloromethane 0.4L and sat. bicarbonate solution 0.5L with some additional water (100mL). The aqueous phase was re-extracted three times with dichloromethane (3x250mL). The combined organic extracts were filtered to break the emulsion, washed with sat. bicarbonate 0.5L, dried (MgSO4) and evaporated. The residue was purified on a column of silica 250g in hexane-EtOAc 3:2 mixture. The purified product (7.5g of a pale-yellow oil) was re-distilled at reduced pressure , b.p. 105-110C/20 Torr. Y=6.307g (48%) of a colorless liquid.
1H(CD3CN, 400MHz): 8.902(s, 1H), 4.409(q, 7.1Hz, 2H), 2.482(s, 6H), 1.364(t, 7.1Hz, 3H)
Note: On cannot be careful enough when working with methyl triflate. The vapor inhalation can cause lethal lung edema, skin absorption will cause painful blisters and the long-term effect is genotoxicity and cancer. Be careful when opening the MeOTf ampule, work with the stuff only in the hood. Evaporating some concentrated ammonia can be used to decontaminate the rotavap after the methylation step. Leave the MeOTf syringe to dry up in the back of the hood. Use double gloves. Do not try to clean a MeOTf spill – evacuate.
Org Prep Daily 
MeOTf doesn’t sound a very green reagent does it?
I suppose it’s like HF… CAS 7664-39-3 (which can dissolve bones…)… there are only occasional (current) viable alternatives available for the applications its wanted for…
e.g. “Hydrogen fluoride is toxic and can be fatal if even small amounts are ingested or absorbed through the skin. HF burns require immediate treatment beginning with washing with water but specialized care is indicated. HF acid burns are not similar to those produced by hydrogen chloride (HCl), or other common acids. Onset time of symptoms of HF burns are proportional to concentration. Above 50% instantaneous effects are apparent. Between 20% and 50% clinical symptoms may not appear for one to eight hours. Concentrations below 20% may not result in symptoms for 24 hours.
Entry routes include inhalation, ingestion, skin and eyes. Aside from burns to the eyes, skin, lungs, or digestive tract, the lowering of serum calcium (hypocalcemia) is one of the most serious consequences of HF exposure. As the free fluoride ion penetrates the skin it binds serum calcium forming covalent, nearly insoluble calcium fluoride (CaF2). This has effects on nerve conduction and can lead to extreme throbbing pain, metabolic changes, and even death.”
With MeOTf – It’s all a question of Good Lab Practice… and CAUTION if in doubt.
Comment by Mark C R (Chemist) UK — February 26, 2007 @ 9:16 am
Actualy there is a much safer, non-volatile alternative for MeOTf – it is trimethyl oxonium tetrafluoroborate (or hexafluoroantimonate). The cost on multigram scale can be an issue though and permissible solvent choice is narrow. Then there is diazomethane…not nice, and TMS-diazomethane.
Hard-electrophilic alkylation agents are far more mutagenic than soft alkylators – because O-alkylated nucleic bases are easier to misread than N-alkylated ones. But the acute toxicity is usualy related to lung damage. Volatility is a big problem. MeOTf is a close cousin of Magic Methyl, FSO3Me. People ended up in intensive care on respirator after working with “Magic Methyl.”
By the way, green chemistry is not my favorite field – so if you want to go off-tangent, please try to be either interesting or funny or at least irritating in a productive sense. Also, I have removed the duplicate reference to your blog that you put in your previous post. Trying to plugg yourself too obviously will get you tagged as a spammer.
Comment by milkshake — February 26, 2007 @ 9:32 am
Yes, Magic Methyl came up during my reading… I suppose the methylating strength relates to the leaving group effect of Triflates…?
Didn’t know about trimethyl oxonium tetrafluoroborate. I was considering others but I supposed that you would say the alkylating strength would be insufficient or created the potential for side products….So thanks anyway!
Sorry to hear Green Chemistry isn’t your cup of tea, or on your side of the Atlantic – coffee! I suppose you get a rush from handling the nasties! My particular favorites have to be either phosgene or thionyl chloride – both classics. I’ll tryto be either “funny” or “interesting” … even tho its probably somewhat something of an OXYMORON. I’m sure even the most fantasitical people in the world find it difficult to be either!
{I edited out all your annoying fonts and spacing. Your drivel will be next. Cheers, Milkshake}
Comment by Mark C R (Chemist) UK — February 26, 2007 @ 9:57 am
After 11 hours of ambient stirring, do you think there is any unchanged methyl triflate? I’ve done refluxes of hard electrohpilic alkylating agents, and I’ve always assumed that due to the innate reactivity of the alkylating agent, there could not be much unchanged reagent left over.
Of course, this does not stop me from doing a basic quench of the reaction before working up. I’d much prefer to be absolutely safe rather than having my lungs being drained with a needle.
Comment by Tom — February 26, 2007 @ 11:00 am
You are right, there was not much excess of MeOTf. Caesium carbonate/bicarbonate should eat it over time.
Comment by milkshake — February 26, 2007 @ 11:20 am
Off-topic post:
Milkshake, you seem to have a wide an varied amount of experience regarding synthetic organic chemistry. I am wondering, obviously, one can read Carey & Sundberg/Boger/etc and increase their knowledge of reactions and organic chemistry on paper. However, how do you feel is the best way is become an excellent practicing organic chemist? Should one simply put their head down and attempt all of the transformations they can in lab to gain experience?
For example, in your latest prep, all of the chemistry I easily understand. However, I have never personally prepped any nitrogen heterocycles.
Thanks for any insight you have.
Comment by Tom — February 26, 2007 @ 4:26 pm
milkshake: thank you thank you thank you. (glad i’m not the only one who’s easily annoyed)
Comment by Ψ*Ψ — February 26, 2007 @ 7:27 pm
I didn’t plan on deleting people’s comments – but in this case it felt really good. I think I am gradually getting the taste for it.
Comment by milkshake — February 26, 2007 @ 11:50 pm
Tom, thank you for your comment – I wrote the next post as the answer to your question. You know, I am not very succesful in my chemistry career because I screwed up. But I like doing chemistry.
When I hear somebody like Brian Stoltz or Dave McMillan giving lecture and see that what they have done was pretty original and accomplished in a short time, I realize why they are in the first league – and I am not. But one can have fun playing friendly county matches, even if being a pro can be more fun (and fame and money). Once you stop worrying about getting all the way to the top, you can relax and watch the scenery and enjoy the hike.
Comment by milkshake — February 27, 2007 @ 2:29 am
Oh Ho! Pyrimidines! I have not seen this type of amidine cyclization since my days as a molecular recognition guy. Good stuff. I was always amazed at the chemical shift of the proton on C2, always seemed a little farther downfield than it should be.
Why make the methyl ethyl, why not the mesylate or the tosylate, you might increase the yield of the cyclization (which I always found crappy with non-electron rich amidines).
Thanks for this one.
BTW, How are you not successful in your career? You like what you do and are employable… seems good to me. Life is a whole lot more than just the job.
Comment by Milo — February 27, 2007 @ 7:57 am
My career is fine because I am not doing any. I am pretty content – having a good boss and a good project and pleasant and fun colleagues in the lab plus enough research money to buy stuff and a good salary and decent job security for the next few years and laid-back atmosphere – and also I can play little on side with some Pd catalysts, so things can’t get much better.
You are absolutely right, methyl is not optimal, and the formamidine is falling apart in ethanol during the reaction – but I was following a reaction scheme from Astra-Zeneca Bioorg Med Chem Lett paper, and they mentioned 35-50% depending on the amidine so it was not so bad. But sulfonyl should be much better. Maybe less messy to work-up, too. (I had to re-distill the product even after purifying the mix on a fat silica column, so it was little tedious.)
How is your life- from your posts I see that it is not bad at all, at the mysterious company X. Also, do you know one can buy a pretty decent molecular model sets from Aldrich catalog – it is not very precise as computer model minimisation but rotating the bonds to see where they clash is lot quicker 🙂
Comment by milkshake — February 27, 2007 @ 8:09 am
Milkshake ~ Before magic methyl was pulled from commercial sale, were there any anions or nucleophiles that absolutely required such a reactive methylating agent? It seems as if utilizing magic methyl in many cases would be regarded as sheer overkill.
Comment by Tom — February 28, 2007 @ 1:43 am
You are right, it is usualy overkill but such hot reagent can have advantage of improved O versus C selectivity (when alkylating enolates), milder reaction conditions or a cleaner reaction mixture. I was making triethyloxonium tetrafluoroborate (the OrgSyn procedure is very easy) and the alkylations with it were a joy to behold – that is, until my triethyloxonium stock solution started decomposing.
I think Magic Methyl has no advantage over MeOTf, it was just popularized before MeOTf became available.
Comment by milkshake — February 28, 2007 @ 2:44 am
Things are going quite well at company X. I have found that working on 0.5 – 2.0 kg scale to e really scary at first, but once you get the idea that heat is hard to remove and pressure builds up fast, then it is not so bad. I am fortunate in that each project I am on has me learning new chemistry and reactions, some of which I am still shocked they work (like PPA mediated cyclizations). I am still getting used to the fact that the people who dole out the budgets have no idea what I really do. I guess that is business for ya.
I do have a set of models, but they are so cheap… I am actually pushing for a good set of harvard CPK ones. We have the money… 🙂
Comment by Milo — February 28, 2007 @ 9:21 pm
Maybe a silly question: why do you need to methylate ethyl diacetoacetate to get the pyrimidine?
Comment by diketene — March 3, 2007 @ 1:14 am
if you don’t cover that OH, you will get only enolate salt formation and no cyclization; heating to bring about dehydratation by brute force does not help because the formamidine starts falling apart at lower temperatures
Comment by milkshake — March 3, 2007 @ 3:20 pm
[…] was written before, but I found it today. From Org Prep Daily: On cannot be careful enough when working with methyl triflate. The vapor inhalation can cause […]
Pingback by The Futile Cycle » Blog Archive » Interesting Chemistry Quote of the Day — March 13, 2007 @ 12:15 pm
Hello Milkshake, I’ve read in some papers that they quenched MeOTf with MeOH. Do you think that this could be enough? I guess from what you are saying excess of aqueous NH4OH is the best for quenching it after the reaction is done. If yes, how long stirring of this quenching do you think is needed? (Is the reaction slow?)
Comment by Alex — December 6, 2009 @ 10:20 pm
the reaction with ammonia should be very fast at room temp – nearly instant.
Comment by milkshake — December 7, 2009 @ 3:03 pm