Synthesis of 4-methoxy-3,5-dinitrobenzaldehyde: a correction to supposed tele nucleophilic aromatic substitution

Combretastatin Dinitrogen-Substituted Stilbene Analogues as Tubulin-Binding and Vascular-Disrupting Agents

“…The synthetic strategy that allowed the preparation of the combretastatin dinitrogen derivatives utilized a Wittig reaction as a key step to form the requisite Z -stilbenoid. Accordingly, the Z -stilbenoids were prepared by reacting 3,4,5-trimethoxybenzylphosphonium bromide 2 (Scheme ) , with commercially available 3,5-dinitro-4-methoxybenzaldehyde along with aldehydes 6 and 7 (Scheme ) , using NaH as the base to generate the ylide (Scheme ). The Z -alkenes were separated from their corresponding E -isomers by flash chromatography to afford stilbenes 8 − 10 in moderate yield.…”

“…Bromide 3 was hydrolyzed to benzyl alcohol 4 , which upon treatment with PCC, afforded the intermediate benzaldehyde 5 . Nitration of 4-methoxy-2-nitrobenzaldehyde ( 5 ) afforded both 2,5- and 2,3-dinitrobenzaldehydes ( 6 and 7 , respectively), which were separated by column chromatography. Yields of aldehydes 6 and 7 decreased considerably when the reaction was stirred for more than 10 min, due to the formation of carboxylic acids, which complicated product separation.…”

“…4-Methoxy-2,5-dinitrobenzaldehyde (6) 25,29 and 4-methoxy-2,3dinitrobenzaldehyde (7). 25,29 At 0 °C, aldehyde 5 (1.53 g, 8.45 mmol) was dissolved in concentrated sulfuric acid (25 mL), to which 7 mL of a precooled (0 °C) mixture of fuming nitric acid (5.32 g, 84.5 mmol) and concentrated sulfuric acid (5.29 g, 54.0 mmol) was slowly added. After stirring for 10 min, the resulting solution was added dropwise into ice-water (approximately 100 mL).…”