DABCO, 1,4-diazabicyclo[2.2.2]octane 4.5g was added to a mixture of 2-hydroxy-5-methoxybenzaldehyde 26.60g (174.8 mmol) and neat acrylonitrile 20mL. The mixture was diluted with additional acrylonitrile 40mL (5.2 eq. total) and refluxed on a 110C oil bath for 5 hours. (Note 1,2). The reaction mix was cooled to RT, diluted with ether 0.5L, shaken with 10% NaOH aq solution 250mL for 5 min then separated. The org phase was washed sequentially with water (250mL), 0.5M sulfuric acid (250mL) and then more water (2x250mL). The aqueous phases were re-extracted with ether (250mL). The combined org. extracts were dried (MgSO4) and evaporated. The solidified residue was dried on highvac. The crude product (a yellow solid, 30.2g) was re-crystallized from methanol (140mL, at 0C overnight, rinse with chilled MeOH) to provide 19.223g of a pure material (98%+) as light-yellow crystals. Evaporating the supernatants and re-crystallising the residue from methanol (50mL, -20C overnight) provided a second crop, 2.827g (96% pure by HPLC). A third crop 1.998g (97% pure) was obtained from the second supernatants (evaporation residue recryst from MeOH 20mL, -20C). The combined yield was 24.048g (73.5% th)
1H(d6-DMSO, 400MHz): 7.537(br s, 1H), 6.896(m, 3H), 4.803(d, 1.3Hz, 2H), 3.714(s, 3H)
24.00g of the nitrile from previous step (128.2 mmol) was combined with aq. solution of NaOH 40g in water 400mL(total volume). The slurry was stirred vigorously under reflux on a 120C bath for 5 hours. Charcoal 1g was added, the mix was re-heated to reflux briefly, then cooled to ambient temperature and filtered (the charcoal was washed with additional water until the filtrates were no longer yellow). The combined filtrates were made strongly acidic with conc. HCl (150mL, exothermic), the resulting slurry was cooled on ice bath, the precipitate was collected by filtration, washed thoroughly with water, dried by suction and then on highvac. The crude acid was dissolved in refluxing acetonitrile (0.6L), allowed to sit for 5 min, then rapidly filtered through a large Buchner funnel while hot and the Buchner funnel was rinsed with additional hot MeCN (approx 10mL), the combined filtrates were re-heated to full dissolution and the mix was allowed to crystallize overnight. Filtration and a rinse with cold MeCN provided the first crop 18.546g as golden-yellow needles. The second crop 4.392g was obtained by evaporating the supernatants and re-crystallising the residue from MeCN 120mL. The third crop 0.888g was obtained analogously (from second supernatants, re-cryst from MeCN 20mL, yellow plates). The combined yield was 23.826g (90%Y) of a pure acid.
1H(d6-DMSO, 400MHz): 12.821(br s, 1H), 7.422(s, 1H), 6.957(d, 2.9Hz, 1H), 6.849(ddABX, 8.7Hz, 2.9Hz, 1H), 6.785(dAB, 8.8Hz, 1H), 4.827(d, 1.4Hz, 2H), 3.704(s, 3H)
Note 1: Acrylonitrile is a potent irritant - and a good carcinogen too. Use gloves, avoid the vapors. Asthmatics keep their inhaler at hand.
Note 2: The original procedure calls for 20 h reflux. In my hands there was no further change after 3 hours reflux on a 110C bath - so I eventually stopped it at 5 hours because DABCO also catalyzes acrylonitrile dimer formation. Fluka acrylonitrile (BHT stabilised material) was used straight from the bottle.