o-Formylation of electron-rich phenols with dichloromethyl methyl ether and TiCl4O Garcia, E Nicolás, F AlbericioTet. Lett. 44(27), 4961-4963 (2003)
(
https://www.thevespiary.org/rhodium/Rhodium/pdf/o-formylation.dcmme.ticl4.pdf)
DOI:
10.1016/S0040-4039(03)01168-7
Abstract - o-Formylation of electron-rich phenols is accomplished with dichloromethyl methyl ether and TiCl4. The reaction gives excellent yields, good regioselectivity and does not leading to diformylation.
General procedure for the formylation reaction - Reagent were used as received without further purification. Dichloromethane (DCM) was passed through an alumina column, stored over CaH2 under an Ar atmosphere, and protected from the light.
A solution of the appropriate phenol (20-150 mmol) in DCM (1.5 mL/g phenol) was purged with N2, cooled with an ice bath, and TiCl4 (2.2 eq to obtain
1 and
2 and 5 eq to obtain
3-5) was added dropwise over 15-30 min. The reaction mixture was left to react for 30-60 min. Dichloromethyl methyl ether (1 eq) was added over 15 min and the mixture left to react for a further 1-2 h. The reaction was quenched by the addition of saturated NH4Cl solution and the mixture was left to stand for 1 h. The organic phase was separated and washed with 0.1 N HCl, saturated with NaHCO3 solution, and brine. The solution was dried over MgSO4, filtered, and the solvent evaporated under reduced pressure. The purified products were homogeneous by HPLC (nucleosil C18, 250x40 mm, 10 µm; linear gradient of CH3CN (+0.036% TFA) into H2O (+0.045% TFA) at 1.0 mL/min flow rate; 220 nm), and there were characterised using different physical techniques.
1 - 2-formyl-3,5-dimethoxyphenol
2 - 2-formyl-3,5,6-trimethylphenol
3 - 2-formyl-3,4,5-trimethoxyphenol
4 - 2,3-dihydro-2,2-dimethyl-4,5,6-trimethoxybenzofuran-7-carbaldehyde
5 - (8-formyl-3,4-dihydro-2-methyl-5,6,7-trimethoxy-2H-1-benzopyran-2-yl)-acetic acid
Pitty that dichloromethyl methyl ether is rather expensive. There have been more posts in the past concerning this formylation method. I suggest using TFSE for those who show interest in the reaction.
