Synthesis of quinolin-2-ones by an intramolecular Knoevenagel condensation and by tandem Michael–Knoevenagel heterocyclization

Abstract

Compounds containing the quinolin-2-one fragment have already been studied systematically as subjects of medicobiological investigations for more than 50 years. Since then it was discovered that quinolin-2-ones as structural units, form part of the composition of a series of natural alkaloids [1]. The investigations led to a remarkable result, but only in practically the last 10-12 years, when new biological targets were discovered and test systems based on them were designed and in practice highly coeffective screening was embodied in the search for new medicinals. It was established that derivatives of quinolin-2-ones may display properties of nonsteroidal selective androgen modulators [2-4] and may show effective action against hepatitis B [5], act as inhibitors of acyl coenzyme A and cholesterol acyltransferase and increase the permeability of calcium activated K + channels [6, 7], display high antiproliferative activity [8][9][10][11] and the ability to bind to 5-HT 3 receptors [12], to receptors of antibiotics [13], and are inhibitors of various types of kinase [14][15][16][17], of farnesyl transferase [18], and affect erectile dysfunction [19]. The established broad spectrum of biological activity of quinolin-2-ones derivatives studied up to the present time, on the one hand, stimulated the search of new medicinals of various profile based on them, and on the other, made urgent the problem of synthesizing new representatives of this class with the prospect of developing for them characteristic forms of biological activity and the potential of using them for practical purposes.For the synthesis of new derivatives of quinolin-2-ones, we turned to the Knoevenagel intramolecular condensation using as precursor the corresponding derivatives of ortho-aminoacylbenzenes. This route to the synthesis of quinolin-2-one, comprising the heterocyclization of 2-(acetylamino)acetophenone under the action of aqueous alcoholic alkaline solution, was used for the first time in [20]. However, many years passed before a series of quinolin-2-ones was synthesized in a similar manner [21,22]. In all probability, insufficient attention to this method of synthesis was linked with the difficulties of obtaining the starting ortho-aminoacylbenzenes.

Intramolecular cyclization of N-(3-oxoalkenyl)phenylacetamides: synthesis of 3-phenyl-2(1H)-pyridones

“…The cyclization of o-acylaminophenones 1 is well known as the Camps reaction and has been used for the synthesis of 2(1H)-quinolinones 4 and 4(1H)-quinolinones 5 since the 19 th century. [17][18][19][20][21][22] The regioselectivity of the reaction depends on the C-H acidity at the -carbamoyl position of amides 1. Increasing the -carbamoyl acidity facilitates cyclization of amides 1 to 2(1H)-quinolinones 4.…”