Knoevenagel condensation of 2-cyanoacetamide with 6-nitroveratraldehyde; 2-cyano-3-(4,5-dimethoxy-2-nitrophenyl)acrylamide

Vedran Hasimbegovic ([email protected]),
A contribution from the Dunne Group, Mälardalen University (Sweden)

Chemicals Used
2-propanol, analytical grade (Scharlau) Methanol, analytical grade (Scharlau) 2-cyanoacetamide, 99% (Aldrich) 4,5-dimethoxy-2-nitro-benzaldehyde, technical grade (Aldrich) Piperidine (Labassco)

Procedure
To a slurry of 6-nitroveratraldehyde (5 g, 23.7 mmol) in methanol (50 mL) there was added 2-cyanoacetamide (2.2 g, 26.2 mmol), followed by piperidine (10 drops). The mixture was heated to reflux for 2 h, then cooled in an ice bath and finally filtered with suction. The intense-yellow crystals were washed with i-PrOH (30 mL) and air-dried to yield 5.6 g (100 %) of 2-cyano-3-(4,5-dimethoxy-2-nitrophenyl)acrylamide: mp 259-260 °C (literature[1]: 265-266°C)

Author's Comments
The reaction was done twice, first time on ~2.5 mmol scale yielding only ~60%. The initially difficult-to-stir slurry becomes somewhat stirrable once heated up. TLC was run with EtOAc pre-treated with a couple of drops glacial acetic acid. This proved to be a nice trick in order to eliminate the �tail� behind the product-spot (which appeared with plain EtOAc). The starting material contained impurities (two very weak spots), the given Rf value corresponds to the most intense one.

Data
1H NMR 300 MHz (DMSO): 8.53 (1H, s CH=C), 7.93 (2H, d, amide), 7.81 (1H, s, ArH), 7.50 (1H, s, ArH), 3.95 (3H, s, OCH₃), 3.94 (3H, s, OCH₃) TLC with EtOAc (containing 5 drops AcOH) as eluent: Rf(6-nitroveratraldehyde): 0.9 (3 spots), Rf(product): 0.72 (one spot).

Lead Reference
[1]: Journal of Medicinal Chemistry, 1980, 23, 262-269

Other References
Patent; Pfizer Inc.; FR 2225166; 1974; DE 2418498; Chem.Abstr.; 82; 73015.

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