Formaldehyde → 6-Hydroxymethyl-nicotinic acid methyl ester

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Dimethylpyridine-2,5-dicarboxylate (II, 3.6 g, 18.4 mmol) was dissolved in THF/MeOH/CH2Cl2 (1:2:1 v/v, 120 ml). Calcium chloride (7.0 g, 63.1 mmol, 3.4 eq) was added in one portion. The resulting clear light yellow solution was cooled to 0° C. NaBH4 (0.85 g, 22.5 mmol, 1.2 eq) was added portion wise. The mixture was stirred at 0° C. for 1.5 hours, at the end of which TLC (ethyl acetate/hexanes 1:1) indicated completion of reaction. Aqueous formaldehyde (37 wt %, 4.5 g, 55.5 mmol, 3 eq) in 50 ml ice-water was added dropwise. The mixture was extracted with CHCl3 (3×150 ml). The combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and then passed through a silica gel pad (eluent 5% MeOH in CH2Cl2) to afford the desired product (2.95 g, 96%) as a light yellow waxy solid. MS-ESI m/z 168.12 (M+H)+; 1H NMR (CDCl3) δ 9.17 (d, J=1 Hz, 1H), 8.30 (dd, J=2 and 8.5 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 4.84 (d, J=5 Hz, 2H), 3.96 (s, 3H), 3.63 (t, J=5 Hz, 1H) ppm.

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