Cyclocondensation of ethyl 3,3-diaminoacrylate with aromatic ketones and nitriles containing a labile halogen atom in the ortho position

Abstract

The cyclocondensation of aromatic o-halo ketones and o-halo nitriles with ethyl 3,3-diaminoacrylate proceeds as the replacement of the aromatic halogen by the α-carbon atom of the enediamine, while the amino group of the enediamine is bound by the α-carbon atom of the ketone or nitrile group.Keywords: aromatic o-halo ketones and o-halo nitriles, 3,3-diaminoacrylate, cyclocondensation.α-Acylacetamidines, which exist in enediamine form, react with aromatic aldehydes and esters containing a labile halogen atom in the ortho position to give predominantly or exclusively condensed aminopyridines [1][2][3]. In the present work, we studied the feasibility of using ketones and nitriles in this reaction and investigated the cyclocondensation of ethyl 3,3-diaminoacrylate (1) with 2-fluoro-5-nitroacetophenone (2) [4], three 5-acyl-4,6-dichloropyrimidines (3a-c) [5-7], and two pyrimidinecarbonitriles (4a,b) [8,9].Acetophenone 2 reacts with diaminoacrylate 1 to give only 3-aminoisoquinoline 5. The structure of this product was confirmed by the 1 H NMR spectrum, which is extremely similar to the spectrum of ethyl 3-amino-7-nitroisoquinoline-4-carboxylate (obtained from 2-fluoro-5-nitrobenzaldehyde [1]). NOE cross peaks are found in the NOESY correlation spectrum between H-5 and the ethoxy group protons.The nature of the acyl group has the predominant effect on the direction of the reaction for 5-acylpyrimidines 3 with diaminoacrylate 1. Aldehyde 3a (R = H) reacts similarly to its 2-methylsulfanyl analog [2] to give pyridopyrimidine 6, albeit in low yield. The structure of 6 was confirmed by 1 H and 13 C NMR Me O F O 2 N NH 2 NH 2 CO 2 Et O 2 N N NH 2 Me CO 2 Et + 2 1 5

Recent advances in the chemistry and biology of pyridopyrimidines

“…1-(4-Chloro-2-methylsulfanyl-pyrimidin-5-yl)ethanone 10 reacted with ethyl 3,3-diaminoprop-2-enoate 9 to produce the pyrido [4,3-d]pyrimidine derivative 11 in 71% yield at room temperature in DMF. At elevated temperature (175 C), the same reaction with chloropyrimidine 12 led in a few minutes to the bisamino derivative 13 in good yield (Scheme 3) [8,9].…”