Novel Amination and 1,2-Amino,hydro-Elimination between 2,3-Diketopyrido[4,3,2-<i>d</i><i>e</i>]quinolines and Primary Amino Compounds

1999-09-30T00:00:00Z (GMT) by Qizhu Ding J. William Lown
A novel amination and 1,2-amino,hydro-elimination reaction occurs between 2,3-diketopyrido[4,3,2-<i>de</i>]quinoline (<b>1</b>, <b>2</b>) 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-<i>de</i>]quinoline to form a 3a,4-dihydro-2,3-diketopyrido[4,3,2-<i>de</i>]quinoline. This dihydro intermediate is immediately oxidized by ambient air to produce the more stable aromatic system, 4-(<i>N</i>-alkyl or aryl)-2,3-diketopyrido[4,3,2-<i>de</i>]quinoline (<b>5</b>−<b>12</b>). In the cases of aliphatic amines bearing a <i>β</i>-proton in THF or chloroform, this 4-(<i>N</i>-alkyl)-2,3-diketopyrido[4,3,2-<i>de</i>]quinoline undergoes a 1,2-amino,hydro-elimination reaction to eliminate an alkene and produce the 4-amino-2,3-diketopyrido[4,3,2-<i>de</i>]quinoline (<b>13</b>, <b>14</b>). In the cases of <i>α</i>-amino acids in aqueous solution, the 4-(<i>N</i>-alkyl)-2,3-diketopyrido[4,3,2-<i>de</i>]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-<i>de</i>]quinoline (<b>13</b>) and the <i>α</i>-keto acid. 2,3-Diketopyrido[4,3,2-<i>de</i>]quinoline (<b>1</b>) can also react with the peptide which contains a primary amino group to form the 2,3-diketopyrido[4,3,2-<i>de</i>]quinoline−peptide conjugate. This novel amination−elimination reaction may underlie the marked cytotoxic potency of the 2,3-diketopyrido[4,3,2-<i>de</i>]quinolines (<b>1</b> and <b>2</b>). As inorganic amino compounds, hydroxylamine and hydrazine can also undergo the nucleophilic addition to 2,3-diketopyrido[4,3,2-<i>de</i>]quinoline (<b>1</b>, <b>2</b>) to produce 4-amino-2,3-diketopyrido[4,3,2-<i>de</i>]quinoline (<b>13</b>, <b>14</b>) which includes a elimination reaction between C4 and <i>α</i>-nitrogen.