Studies with Polyfunctionally Substituted Heteroaromatics: A Novel Synthesis of Substituted 4,8-Diaminoisoquinolines as Potential Antiparasitic Agents

About the reaction of β‐dimethylamino‐α,β‐enones with active methylene nitriles

“…Malononitrile substitutes the dimethylamnino group to give the intermediate 14 followed by cyclization and ring opening of the formed iminopyran to afford 15, which readily eliminates dimethylamine to afford the final isolable 2-1H-pyridinone derivative 16 (in a Dimroth-type rearrangement). Although the claimed structure 13 and our structure 16 have almost the same elemental and spectral data, however, the d value given by Elnagdi and coworkers [13] to the pyridinone H is 7.95 ppm, which better fits to the H-4 rather than the H-6. A structure like 13 would have revealed this H-6 signal much up field at %6-7 ppm.…”

“…A structure like 13 would have revealed this H-6 signal much up field at %6-7 ppm. The 13 C NMR data given in [13] are wrongly interpreted. They assigned the value 116.64 ppm to the C-4, which points out that no methyl group is attached to this carbon, because attached methyl group at the fourth position would have shifted this Active Methylene Nitriles value dramatically low field (>150 ppm); and the same words can be said on the value given to C-6 d ¼ 148.54, which is too much down field value to a simple CH (%90-100 ppm) and this means that the methyl group is attached to this carbon (C-6).…”

“…Furthermore, Elnagdi and coworkers [13] have reported the reaction of 3-acetylamino-4-dimethylaminobut-3-en-2-one 11 (obtained from the reaction of acetylaminoacetone with DMFDMA) with malononitrile 2a and assumed the same scenario of condensation to give 12, which is cyclized to 13 (Scheme 2).…”

“…In one article, it was assumed that malononitrile 2a is first hydrolyzed to cyanoacetamide by the water present in the solvent [12], which then condenses with the carbonyl group of 1a-c to afford 3a-c. In the other article, it was assumed that the condensation takes place first and then the water resulting from the condensation hydrolyzes one of the cyano groups in the products of 2a but do nothing with the products of 2b to afford the amides 3a-c [13]. Then, compounds 3a-c were cyclized to afford the 2-1H-pyridones 4a-c.…”

“…The reaction of enaminones with active methylene nitriles represents one of the strategies for the preparation of 2-1H-pyridone [9][10][11]. 3-Dimethylamino-1-arylpropenones 1a-c have been extensively used in the last years by Elnagdi and coworkers for the synthesis of pyridones [12][13][14]. The reaction of 1a-c with active methylene nitriles (namely malononitrile 2a and cyanoacetamide 2b; Scheme 1) in all these and other publications was based on the idea of a Knoevenagel condensation of the active methylene in 2a or 2b with the carbonyl groups of 1a-c.…”