4-Hydroxy-2-quinolones. 167*. Study of the reaction of ethyl 1-alkyl-substituted 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates with phosphorus oxychloride

Abstract

Thanks to their high reactivity 3-substituted 4-chloro-2-oxo-1,2-dihydroquinolines readily react with many nucleophiles and are of interest for the synthesis of very different products. The most convenient method for their preparation is treatment of the corresponding 4-hydroxy derivatives with phosphorus oxychloride or its mixture with phosphorus pentachloride [2,3]. As a rule, such reactions are readily carried out and proceed to give results as anticipated although sometimes a marked increase in the yields and purities of the final 4-chloro-2-quinolones is only achieved through the addition of basic catalysts to markedly ease the exchange of the 4-hydroxy group for halogen [4]. Up to this time it has not been considered that the 1-N-alkyl substituents are affected by this and their removal is only possible under much more forcing conditions, e.g. by fusion with phosphorus pentachloride [2]. For this reason it is likely that a detailed study of the features of the reaction of 1-substituted 4-hydroxy-2-quinolones to their 4-chloro derivatives using phosphorus oxychloride has not received the required attention and in the scientific literature one meets a very wide variation in reaction time (from 1 to 16 h) [4][5][6][7][8]. However, in none of these does one find data explaining why a particular reaction times was used. At the same time, experiments carried out by us have shown that, at least in the case of 1-alkylsubstituted 3-ethoxycarbonyl-4-hydroxy-2-oxo-1,2-dihydroquinolines, this factor has an extremely significant effect on the purity of the 4-chloro substituted derivatives obtained. 9520009-3122/09/4508-0952©2009 Springer Science+Business Media, Inc.The behavior noted in the reaction between phosphorus oxychloride and ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate with long N-alkyl substituents (beginning with butyl) serves as the basis for carrying out this type of study. Thus, if after conventionally refluxing the reaction mixture for 1-2 h, the separation of the target reaction product is not carried out immediately but for some reason left to the following day then serious complications can occur namely the formed 4-chloro derivative proves to be very difficult to convert to the crystalline state. Such problems do not arise with an ordinary synthesis hence it is quite apparent that prolonged contact of 1-alkyl-substituted 4-hydroxyquinol-2-ones with phosphorus oxychloride is accompanied not only by exchange of the 4-hydroxy group for chlorine but also by other more profound chemical processes.To resolve this question, chromatographically pure ethyl 1-ethyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (1) was refluxed with phosphorus oxychloride with regular removal of a sample which then underwent chromato mass-spectrometric analysis. N OH Et O O OEt N Cl Et O O OEt N Cl Cl O OEt 1 2 3 POCl 3 + 105°СIt was firstly and unexpectedly revealed that exchange of the 4-hydroxy group for chlorine occurs very rapidly. Even after 5 min the starting ester 1 was not found in the reaction mixture ...