Rhodium (Chief Bee) 10-18-03 00:43 No 465288				Methoxybenzaldehyde Demethylation w/ MgI2*Et2O (Rated as: excellent)
						Regioselective demethylation of 2,6-dimethoxybenzaldehydes with magnesium iodide etherate S. Yamaguchi, M. Nedachi, H. Yokoyama, Y. Hirai Tetrahedron Letters 40, 7363-7365 (1999) DOI:10.1016/S0040-4039(99)01411-2 Abstract Demethylation of asymmetrically substituted 2,6-dimethoxybenzaldehydes with magnesium iodide etherate regioselectively single 6-methoxysalicylaldehydes derived from the more unstable chelation. Magnesium iodide etherate is a mild reagent for the demethylation on a phenolic O-methyl group especially at the position ortho to the carbonyl group.1 In our previous paper,2 demethylation of 5-acetyl-4,6-dimethoxy-2-isopropenyl-2,3-dihydrobenzofuran, having two O-methyl groups at both ortho positions to the carbonyl, gave a single mono-demethylated product (racemic Remiroltm). Herein, we discuss this regioselective demethylation. Demethylation of two symmetric 2,6-dimethoxybenzaldehydes (1a,b) and four asymmetric 2,6-dimethoxybenzaldehydes (1c-e) with magnesium iodide etherate effectively gave single 6-methoxysalicylaldehydes (2a-e), these results are summarized in Table 1. Interestingly, in NOE measurements of the products, irradiation on the methoxy signal caused some increases (+13% in 2c, +7% in 2d, +13% in 2e) in the aromatic proton signals, and these showed the regioselective demethylation on the more hindered O-methyl groups. Demethylation of asymmetric 3-chloro-2,6-dimethoxy-5-methylbenzaldehyde (1f) also gave a single salicylaldehyde, 3-chloro-6-methoxy-5-methylsalicylaldehyde (2f), derived from the demethylation on the chloro-side, not 5-chloro-6-methoxy-3-methylsalicylaldehyde (3f) derived from the demethylation on the methyl-side. The structure of 2f was determined by comparing it with the authentic samples 2f and 3f.3 This regioselectivity might be explained as follows. Each 2,6-dimethoxybenzaldehyde can form an equilibrium of two chelation isomers, unstable A-1 and stable B-1. In the subsequent thermal elimination of methyl iodide (might be a rate-determining step), the elimination may be kinetically more favored from the unstable isomer A-1 than from the stable B-1, via the lower activation. In any case, the demethylation from the isomer, destabilized by steric or electrostatic repulsion, might be kinetically favored. Table 1: Demethylation of 2,6-dimethoxybenzaldehydes (1) with magnesium iodide etherate5 Substrate R3 R4 R5 Reaction Time Product Yield 1a H Me H 1.5h 2a6 70% 1b H C5H11 H 1.5h 2b7 63% 1c Me H H 4.5h 2c4 84% 1d Cl H H 3.5h 2d 94% 1e Cl Me H 4.5h 2e6 68% 1f Cl H Me 3.0h 2f 90% References [1] Yamaguchi, S.; Sugiura, K.; Fukuoka, R.; Okazaki, K.; Takeuchi, M.; Kawase, Y. Bull. Chem. Soc. Jpn. 57, 3607 (1984) [2] Yamaguchi, S.; Takai, M.; Hanazome, l.; Okada, Y.; Kawase, Y. Bull. Chem. Soc. Jpn. 60, 3603 (1987) [3] Compounds 2g and 3g were prepared by chlorination of corresponding salicylaldehydes with sulfuryl chloride, and these details will be reported soon in our synthetic study on mycochromenic acid. [4] Details will be reported soon in our synthetic study on mycochromenic acid. [5] General procedure for demethylation: To a benzene solution of magnesium iodide etherate, prepared from magnesium metal (102 mg, 3.99 mmol), iodine (936 mg, 3.62 mmol), ether (6 ml), and benzene (10 ml), was added a solution of 2,6-dimethoxybenzaldehyde (3 mmol) in benzene (30 ml); the mixture was refluxed, treated with 10% hydrochloric acid, and extracted with benzene, and the product was purified on a silica gel column. [6] Details will be reported soon in our synthetic study on cannabiorcichromenic acid. [7] Yamaguchi, S.; Shouji, N.; Kuroda, K. Bull. Chem. Soc. Jpn. 68, 305 (1995)