An Expedient Route to 3-Methoxy-2-furaldehyde

Abstract

An expedient route to 3-methoxy-2-furaldehyde is presented.

Key words

furans - aldehydes - heterocycles - nucleophilic substitution - Diels-Alder reaction

References and Notes

• 1 For a review, see: Kappe CO. Murphree SS. Padwa A. Tetrahedron  1997,  53:  14179 
• 2a Charest MG. Lerner CD. Brubaker JD. Siegel DR. Myers AG. Science  2005,  308:  395 
• 2b Charest MG. Siegel DR. Myers AG. J. Am. Chem. Soc.  2005,  127:  8292 
• 2c Brubaker JD. Myers AG. Org. Lett.  2007,  9:  3523 
• 2d Sun C. Wang Q. Brubaker JD. Wright PM. Lerner CD. Noson K. Charest M. Siegel DR. Wang Y.-M. Myers AG. J. Am. Chem. Soc.  2008,  130:  17913 
• 3a Lyapkalo IM. Webel M. Reißig H.-U. Eur. J. Org. Chem.  2001,  4189 
• 3b Mesiter C. Scharf H.-D. Synthesis  1981,  733 
• 3c Mesiter C. Scharf H.-D. Synthesis  1981,  737 
• 4a Ly ND. Schlosser M. Helv. Chim. Acta  1977,  60:  2085 
• 4b Antonioletti R. D’Auria M. De Mico A. Piancatelli G. Scettri A. J. Chem. Soc., Perkin Trans. 1  1985,  1285 
• 4c Sornay R. Meunier J.-M. Fournari P. Bull. Soc. Chim. Fr.  1971,  990 

5

Two of the major impurities were tentatively assigned using HPLC-MS and ^¹H NMR as a dimer and trimer likely resulting from side reaction of the starting material with the product.

6

General Experimental: All reactions were performed under a nitrogen atmosphere. ^¹H NMR spectra were recorded using an Oxford ASR400 spectrometer operating at 400 MHz at a probe temperature of 25 ˚C. Assays by HPLC-MS analyses were performed on an Agilent 1200 using a Zorbax C18 column and H₂O-MeCN mobile phases that included 0.1% formic acid. 3-Bromofuran was obtained from Penn Specialty Chemicals and was separated from aqueous materials included for stabilization before use. All commercially available starting materials, reagents and solvents were used as received.
Preparation of 3-Bromo-2-furaldehyde: To a 5-L, 4-neck round-bottomed flask was charged 2-methyltetrahydrofuran (1000 mL) followed by i-Pr₂NH (173 mL, 1.3 equiv). The mixture was cooled to T _i = -10 ˚C and n-BuLi (410 mL, 2.5 M in hexanes, 1.0 equiv) was charged into a 1-L addition funnel. The n-BuLi was added dropwise to the reactor over 15 min while keeping the batch temperature below -10 ˚C. The resulting pale yellow solution was cooled to -45 ˚C and kept for 10 min at that temperature. 3-Bromofuran (neat, liquid, 150 g) was charged while maintaining batch tempera-ture below -40 ˚C. The dark brown suspension was stirred at -45 ˚C for 30 min and DMF (108 mL, 1.4 equiv) was added dropwise over 10 min via addition funnel while observing an exotherm. Temperature was maintained below -40 ˚C during addition. The reaction was completed after 10 min at -40 ˚C and the batch was quenched by the addition of 25% citric acid solution (1500 mL, w/v). The layers were separated and the aqueous layer was extracted once with EtOAc (1000 mL). The combined organics were subse-quently washed with H₂O (500 mL) and then with sat. aq NaCl (500 mL). The organic layer was concentrated under reduced pressure at 30 ˚C to give a dark brown oil (178 g) along with some visible solids. The residue was diluted with MTBE (100 mL) and filtered through a medium fritted funnel. An additional portion of MTBE (100 mL) was used to wash the filter. The filtrate was concentrated to give 3-bromo-2-furaldehyde (164 g, 92%) as a dark brown oil.
Analytical data were in accordance with those of a commercial sample.
Preparation of 3-Methoxy-2-furaldehyde: To a 50-L reactor equipped with an overhead stirrer, nitrogen inlet and reflux condenser was added anhyd MeOH (20 L) followed by NaOMe (25 mL, 25 w/w% solution in MeOH) to assure a basic media at start of addition. The solution was heated to T _i = 64 ˚C. 3-Bromo-2-furaldehyde (1034 g) was charged to a 1-L addition funnel and NaOMe (5 L, 25 w/w% in MeOH, 3.7 equiv) was charged into a second funnel. The NaOMe and 3-bromofurfural in the respective addition funnels were simultaneously added dropwise over 5 h, and the mixture was subsequently stirred at 64 ˚C for 13 h. After the reaction was complete, the mixture was cooled to 20 ˚C and stirred at that temperature for 3 h. The temperature was lowered further to -30 ˚C and 12% aq AcOH (10 L) was added resulting in a rise of the temperature to about 5 ˚C. Most of the MeOH (about 23 L) was removed at reduced pressure at 35 ˚C and the remaining mixture (about 12 L) was extracted with CH₂Cl₂ (2 × 10 L). The combined organics were washed with half-saturated aq NaHCO₃ (10 L). The organics were concentrated at reduced pressure at 25 ˚C to give a black crystalline material. Reslurry in MTBE (4 L) and hexane (4 L) gave about 250 g of product as filterable solids. Additional material (260 g of black amorphous material which was stuck to the flask) along with 120 g from evaporation of the mother liquors was combined, dissolved in CH₂Cl₂ (1.5 L) and passed through silica gel (500 mL) which was further eluted with 1.5 L CH₂Cl₂. The CH₂Cl₂ was evaporated and the resulting solids were combined with the first solids (250 g) followed by suspending the solids in MTBE (3 L). Hexanes (3 L) were then added over 5 h at r.t. After stirring for an additional 17 h the slurry was cooled to 0 ˚C. The solids were collected by filtration and provided after drying 3-MeO-2-furaldehyde (440 g, 59%) as a brown solid.
Analytical data were in accordance with those described in the literature.^²c