(Chief Bee)
11-01-02 15:28
No 375367
(Rated as: excellent)
Preparation of 4-Formyl-3,5-dimethoxyphenol (1).
The large-scale procedure described here is an adaptation of the Vilsmeier formylation approach described by Barany et al.1,10 In a typical 5 mol scale preparation, DMF (582 mL, 7.52 mol) is added dropwise to a stirred 0 C solution of 3,5-dimethoxyphenol (6, 770 g, 5 mol) in POCl3 (936 mL, 10.04 mol). After stirring at room temperature for 16 h, hydrolysis of the resulting chloroamine intermediate, and precipitation of crude product, 4-formyl-3,5-dimethoxyphenol (1) is obtained as the major product along with the reported byproducts 2-formyl regioisomer 7 and the bisformylated derivative 8 (Scheme 1). We found that during large-scale preparation, slow addition of DMF, temperature control, and vigorous mechanical stirring were essential to minimize the formation of these byproducts and to achieve consistent, reproducible results. Scheme 1. Preparation of 4-Formyl-3,5-dimethoxyphenol (1)a a Reagents and conditions: (a) POCl3, DMF, 0 C to room temperature, 16 h; (b) CHCl3, 1 L, brief multiple treatments, 56% for two steps.
The convenient purification described here is effective owing to an earlier observation by Barany1 that compounds 1, 7, and 8 have different solubility properties. During preliminary studies, sample preparation of the crude product mixture for NMR analysis revealed that the chloroform solubility of the byproducts 7 and 8 is much higher than that of the desired 4-formyl positional isomer 1. This observation prompted us to pursue trituration as a simple and scalable method for large-scale purification of 4-formyl-3,5-dimethoxyphenol (1). In practice (5 mol scale), brief trituration of the crude Vilsmeier product mixture with chloroform (3 treatments, 1 L/treatment) followed by evaporation of excess solvent provides 1 as a pale orange powder (513 g, 56% overall yield) in greater than 95% purity (1H NMR, HPLC). The progress of the purification can be followed easily by TLC, 1H NMR, or HPLC analysis of either the residual solids or the chloroform solution during trituration. This simple, scalable trituration step eliminates the need for the large-scale aqueous/organic extraction and recrystallization steps employed in earlier procedures. This rapid and reliable procedure is now used routinely in our labs for multi-hundred-gram preparation of 4-formyl-3,5-dimethoxyphenol (1).
4-Formyl-3,5-dimethoxyphenol (1).
To a 4 L three-neck round-bottomed flask equipped with a mechanical stirrer, a 1 L addition funnel, and a thermometer were added 770 g (5.00 mol) of 3,5-dimethoxyphenol (6) and 936 mL (10.04 mol) of POCl3 under argon. After being stirred for 10 min, the mixture was cooled to 0 C and 582 mL (7.52 mol) of anhydrous DMF was added dropwise via the addition funnel over 4 h. It was crucial that the internal temperature remain below 10 C during the entire addition period. After the addition, the mixture was allowed to warm to room temperature while stirring. As the reaction progressed, the reaction mixture became very viscous. Therefore, use of a mechanical stirrer rather than a magnetic stirrer is highly recommended. After being stirred at room temperature for an additional 16 h, the reaction mixture was poured into 11.5 kg of ice. Additional water was used to ensure quantitative transfer of the product out of the reaction flask (three 2 L portions). The combined aqueous mixture was allowed to warm to room temperature over 1 h while stirring. NaOH pellets (~1.2 kg) were added until a pH of 6.0 was reached. The resulting precipitate was then collected using a filter funnel and dried in a vacuum oven at 40 C overnight. The collected precipitate was triturated three times with 950 mL portions of CHCl3 to remove the CHCl3-soluble byproducts (2-formyl-3,5-dimethoxyphenol (7) and the bisformylated derivative 8). The remaining solid was then dried in a vacuum oven at 40 C for 24 h to yield 4-formyl-3,5-dimethoxyphenol (1) as a pale orange powder (513 g, 56%). Purity of the product was greater than 95% by HPLC. mp 223-225 C (lit. mp 224-226°C).
Ref: J. Comb. Chem., 3 (1), 97-101 (2001)
