Novel Amination and 1,2-Amino,hydro-Elimination between 2,3-Diketopyrido[4,3,2-de]quinolines and Primary Amino Compounds

Abstract

A novel amination and 1,2-amino,hydro-elimination reaction occurs between 2,3-diketopyrido[4,3,2-de]quinoline (1, 2) and amino compounds which include α-amino acids and peptides which contain a primary amino group. The amino group undergoes nucleophilic addition to the double bond between C3a and C4 in 2,3-diketopyrido[4,3,2-de]quinoline to form a 3a,4-dihydro-2,3-diketopyrido[4,3,2-de]quinoline. This dihydro intermediate is immediately oxidized by ambient air to produce the more stable aromatic system, 4-(N-alkyl or aryl)-2,3-diketopyrido[4,3,2-de]quinoline (5−12). In the cases of aliphatic amines bearing a β-proton in THF or chloroform, this 4-(N-alkyl)-2,3-diketopyrido[4,3,2-de]quinoline undergoes a 1,2-amino,hydro-elimination reaction to eliminate an alkene and produce the 4-amino-2,3-diketopyrido[4,3,2-de]quinoline (13, 14). In the cases of α-amino acids in aqueous solution, the 4-(N-alkyl)-2,3-diketopyrido[4,3,2-de]quinoline undergoes an amino-transferring reaction, via a mechanism similar to the action of pyridoxal, to form the 4-amino-2,3-diketopyrido[4,3,2-de]quinoline (13) and the α-keto acid. 2,3-Diketopyrido[4,3,2-de]quinoline (1) can also react with the peptide which contains a primary amino group to form the 2,3-diketopyrido[4,3,2-de]quinoline−peptide conjugate. This novel amination−elimination reaction may underlie the marked cytotoxic potency of the 2,3-diketopyrido[4,3,2-de]quinolines (1 and 2). As inorganic amino compounds, hydroxylamine and hydrazine can also undergo the nucleophilic addition to 2,3-diketopyrido[4,3,2-de]quinoline (1, 2) to produce 4-amino-2,3-diketopyrido[4,3,2-de]quinoline (13, 14) which includes a elimination reaction between C4 and α-nitrogen.

15N labeling and analysis of13C–15N and1H–15N couplings in studies of the structures and chemical transformations of nitrogen heterocycles

“…The appearance of labeled nitrogen atoms in different amines simplifies the determination of the structures of the reaction products exploiting the analysis of 13 C– 15 N and 1 H– 15 N coupling constants. In that vein, the specifics of the interaction of 2,3-diketopyrido[4,3,2- de ]quinolines 201 with 15 N-propylamine were studied 65 ( Scheme 53 ). The 1 H NMR spectrum of the final product 206* showed signals from two protons that are attached to the 15 N-labeled atom ( 1 J HN 92.5 Hz, Scheme 53 ).…”

STUDIES ON THE REACTIONS OF 2,3-DIKETOPYRIDO[4,3,2-de] QUINOLINES WITH AMINO ACIDS AND AMINO ESTERS

“…Finally, 4-amino-2,3-diketopyrido[4,3,2-cfe]quinoIines were formed 13 . The amino group undergoes nucleophilic addition to the double bond between carbon (C3a) and carbon (C4) to form a dihydro intermediate which is then oxidized.…”

“…The biological evaluation data show that 1ethoxycarbonylmethyl-2,3-diketopyrido[4,3,2-de]quinoline is actively cytotoxic exhibiting a wide spectrum of anticancer activities against 22 cell lines in seven cancer panels with LC50 values less than 9 μΜ, especially in non small cell lung cancer, melanoma cancer, renal cancer, prostate cancer, and breast cancer. We have already reported the novel amination and elimination reaction between 2,3-diketopyridö{4,3,2-cfe]quinolines and a limited group of amines 13 . We have already reported the novel amination and elimination reaction between 2,3-diketopyridö{4,3,2-cfe]quinolines and a limited group of amines 13 .…”

Synthesis andIn vitroAntitumor Screening of Novel 2,7-Naphthyridine-3-carboxylic Acid Derivatives

“…Many of these synthetic 2,7‐naphthyridine derivatives have been reported to possess various biological properties. Cytostatic , antimicrobial , analgesic, and antiphlogistic activities have been found. Methyl 1‐oxo‐2,7‐naphthyridine‐3‐carboxylate derivative (T‐0156) is a potent and selective PDE5 inhibitor, better than sildenafil .…”