Wraith (Stranger)
02-02-04 19:39
No 486065
      Selective methylation of 5-OH-Vanillin with CH3I     

To all whom it may concern.

Selective methylation of 5-OH-Vanillin with CH3I

 SWIM stumbled accidently on this reaction when methylating 5-hydroxyvanillin with CH3I in DMF. He tried to use less than a 100% excess of the expensive methyl iodide (CH3I is not very useful for OH-vanillin, even in that excess) and hoped 3,4,5-trimethoxybenzaldehyde would still form in good yields. It doesn't.

 If the CH3I used is less than 1.25 times than the theoretically required amount for methylation of both OH's on the substrate, the solvent is DMF, acid scavenger: excess Na2CO3 or K2CO3 and reaction temperature 90-110 C, rxn time 8-12 h, the main product is syringaldehyde and can be obtained in pure form after adding water to the cooled reaction mixture (sometimes, needles of the Na salt of syringaldehyde separate, depending on the H2O amount), extraction of the small amount of 3,4,5-trimethoxybenzaldehyde from the basic reaction mixture, acidification, extraction of the hydroxy aldehydes (any suitable solvent may be used, EtOAc, DCM, or Et2O) and recrystallization.

 Yield of syringaldehyde is 60-70% calc. on the used OH-vanillin, after recrystallization, mp is between 107-111 C,  Yield of 3,4,5-TMBA is usually about 10-15%, mp 70 C, from light petroleum.

Experimental

Materials:
3,4-dihydroxy-5-methoxybenzaldehyde (5-hydroxyvanillin)
N,N-Dimethylformamide
Methyl iodide
K2CO3 or Na2CO3


3.36 g 3,4-diOH-5-MeO-BA (20 mmol) (from PhMe, mp 133 C, beige) was dissolved in 15 mL dry DMF, 2.5 g anhydrous Na2CO3 and 1.15 mL (36 mmol) CH3I added under draught, the RB flask fitted with a  reflux condender and held at 100 C on a boiling water bath for 11 h, cooled, diluted with water, extracted 3x with EtOAc, the extracts (which contain some excess CH3I, so care must be taken to prevent its escape) washed 2x with 5% NaOH and then 1x with water, the washes being united with the residual solution that contains the hydroxy aldehydes, then dried on MgSO4 and the EtOAc distilled off into an RB flask containing cc NH3 soln. The oily residue can be recrystallized from light petroleum (80-100 C) to afford 0.51 g (13%) of 3,4,5-trimethoxybenzaldehyde, mp 70 C.

The combined reaction solution and washes are acidified carefully with excess HCl or dil. H2SO4 then extracted 4x with DCM, extracts washed 2x with water, dried on MgSO4 and distilled off. A brown solid crystallizes on cooling. Recrystallization from EtOH or light petroleum yields 2.34 g  (65%) of brownish syringaldehyde, mp 108-110 C. Alkylation with any alkyl halide (100% excess, DMF, K2CO3, 12h, 100 C) yields around 85% of the desired aldehyde.

Methyl iodide is very carcinogenic, use efficient draught throughout the procedure and the workup to prevent any exposure.

Substituting EtBr for CH3I in this synth produces 3-ethoxy-4-hydroxy-5-methoxybenzaldehyde in similar yields, mp is 104-107 C from light petroleum, beige color;  and some 3,4-diethoxy-5-methoxybenzaldehyde (oil at rt)

When the 5-OH-vanillin : EtBr ratio was increased to 1:4, 38% of 3,4-DiEtO-5-MeO-BA and 46% of 3-EtO-4-OH-5-MeO-BA were obtained.


Conclusions

1)SWIM is for the first time in his life grateful for not having access to DMS that instantly methylates every aromatic OH it sees.  

2)We have found an easy, almost-OTC and relatively high-yielding route to syringaldehyde and its derivates that avoids the use of NaOCH3 and strictly anhydrous conditions.
The drawback lies in the toxicity and volatility of the methylating agent, as well as its high costs.

Thanks to the pioneers of the procedures that made vanillin our favourite kitchen spice: Uemura, Antoncho, Vitsh, otto, and, of course, Rhodium, and the many others who have contributed to the works.

References: US Pat. 3962345
Post 297806 (OH-Vanillin)


Wraith
 
 
 
 
    GC_MS
(Hive Addict)
02-03-04 13:33
No 486179
      Really?     

1)SWIM is for the first time in his life grateful for not having access to DMS that instantly methylates every aromatic OH it sees.

I doubt that statement is true.

Advanced clitoris massage specialist. 32 years of experience. PM me for a "sample".
 
 
 
 
    Antoncho
(Official Hive Translator)
02-06-04 06:58
No 486837
      Hey, doesn't the guy deserve some karma for this?     

1st of all, - don't you think that Wraith's post above deserves a karma point?

After all, this topic is HIGHLY interesting.

Did it ever occur to anyone that there currently is NO established at the Hive pathway to 3,5-diMeO-4-AlkO-PEAs other than the one that requires dry DMF and sodium metal?

Then again, MeI is more OTC but unfortunately very dangerous: its toxicity is of the same order that DMS's (if i am not mistaken), but it is significantly more volatile (it's really hard to keep in even a tightly closed container).

So for those of us that are fortunate to have some DMS on hands. 'twould bee very much desirable to have some similar proc. using it instead of MeI.

It would bee interesting to research this topic....


GC_MS, so you say that DMS doesn't instantly methylate all it sees? Can you give some examples/suggestions?


Antoncho
 
 
 
 
    Wraith
(Stranger)
02-06-04 19:24
No 486921
      Suggestions for more safety     

First of all, thank you for the interest! 

According to JACS, vol. 74, pp.4262 (1952) (Post 464821 (imp: "Selective Methylation of 5-hydroxyvanillin", Chemistry Discourse)) DMS is not selective enough for this purpose. SWIM's general impression is that DMS is much more reactive than CH3I, there is e.g. this procedure: ../rhodium/345-tmb.html . Hest methylates the syringaldehyde by stirring in DMF at room temperature for 2 h in his dreams. This one definitely needs 8 h on the boiling water bath when performed with CH3I / DMF.
(Maybe dripping in the DMS slowly would raise the selectivity?)

p-tosic acid methyl ester or trimethyl phosphate would represent a somewhat more friendly choice of methylating agents. Dimethyl carbonate seems to need 150 C to work properly and this can often kill our aromatic aldehydes.

From the viewpoint of safety and availability the best reagent would be NaMeOSO3, by far. Can one alkylate, say, vanillin in acceptable yields with NaMeOSO3 in water as solvent, not in a solid phase with microwaves? Your microwave procedure with KEtOSO3 sounds very interesting, Antoncho, but I doubt good selectivity could be achieved under such violent conditions, and 5-OH-vanillin is supposed to be prone to oxidation.

Wraith
 
 
 
 
    imp
(Newbee)
02-24-04 06:11
No 490746
      Really?     

Wraith: SWIM is VERY surprised with your findings. Especially since the authors of JACS, vol. 74, pp.4262 (1952) mention that they used both MeI and DMS with no success using many different reaction conditions.

SWIM thinks it is much more economical to fully methylate the 5-hydroxyvanillin, then demethylate with H2SO4. Demethylation always gives >93% yield.