O-Alkylation of Salicylaldehyde with Ethyl Bromoacetate and Subsequent Dehydrative Annulation; Ethyl benzofuran-2-carboxylate
SyntheticPage 703
DOI:
10.1039/SP703
Submitted Nov 20, 2013, published Dec 04, 2013
Chemicals Used
Salicylaldehyde (98%, Sigma-Aldrich)
Ethyl Bromoacetate (98%, Sigma-Aldrich)
Potassium Carbonate (99.99%, trace metal basis, Sigma Aldrich)
Acetonitrile (ACS reagent, ≥99.5%, Sigma-Aldrich)
Procedure
To a 1000 mL round bottom flask equipped with large stirbar was added salicylaldehyde (15.26 g, 125 mmol, 1 equiv), MeCN (830 mL, ≈ 0.15 M in the aldehyde), and K2CO3 (51.82 g, 375 mmol, 3 equiv). The solution rapidly became yellow and was stirred for five minutes. After this time, the α-bromo ester1 (25.05 g, 150 mmol, 1.2 equiv) was added all at once, causing the solution to become colorless. The flask was then equipped with a reflux condenser and heated to reflux for 72 h while being vigorously stirred. After this time, the flask was cooled to room temperature and the solids were removed by filtration through a coarse2 fritted funnel. The solids were washed thoroughly with Et2O (250 mL) and the filtrate was transferred to a separatory funnel. Deionized water (≈ 500 mL) was added and the layers were separated. The aqueous layer was extracted with Et2O (2 x 150 mL). The combine ether layers were washed with deionized water (2 x 200 mL), followed by brine (200 mL). The organic layer was dried with Na2SO4 and the solvent was removed3 in vacuo to give the desired ester (14.89 g, 63 %) as a clear yellow-orange oil.4
Author's Comments
1. CAUTION: Powerful lachrymator and highly toxic! Handle with care!
2. A coarse filter funnel is highly recommended as the resulting solids have a tendency to clog finer frits, resulting in very time-consuming filtrations
3. While the ether is removed quiet readily, residual acetonitrile is difficult to remove unless high vacuum is used (> 5 mmHg)
4. Despite the color, the product was pure by NMR spectroscopy and suitable for further reactions. However, if further purity is required, distillation of this compound can be performed under very high vacuum ( > 0.4 mmHg)
Data
1H NMR (CDCl3, 400 MHz) d ppm 1.37 (t, J = 7.09 Hz, 3 H) 4.39 (q, J = 7.09 Hz, 2 H) 7.20 - 7.26 (m, 1 H) 7.37 (ddd, J = 8.44, 7.21, 1.22 Hz, 1 H) 7.46 (d, J = 0.98 Hz, 1 H) 7.53 (dd, J = 8.31, 0.73 Hz, 1 H) 7.58 - 7.63 (m, 1 H)
13C NMR (CDCl3, 100 MHz) d ppm 14.37 (CH3) 61.52 (CH2) 112.36 (CH) 113.80 (CH) 122.85 (CH) 123.81 (CH) 127.03 (CH) 127.61 (C) 145.79 (C) 155.75 (C) 159.60 (C)
GC-MS (EI) 190 ([M]+, 68%) 162 (79%) 145 (100%) 134 (9%) 118 (42%) 89 (68%) 78 (8%) 63 (25%)
Lead Reference
Korthals, K. A.; Wulff, W. D. J. Am. Chem. Soc., 2008, 130, 2898.
Supplementary Information
1H NMR (1H NMR Benzofuran ester.jpg)
13C NMR (13C NMR Benzofuran Ester.jpg)
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Keywords: Benzofuran, Condensation, Cyclization, esters, heterocyclic compounds, nucleophilic, substitution
