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