Regioselectivity in the Multi‐Component Synthesis of Indolizinoquinoline‐5,12‐dione Derivatives

Abstract

The one-pot cyclisation to form the indolizinoquinoline-5,12-dione ring system has been investigated starting from 6,7-dichloroquinoline-5,8-dione by reaction with pyridine and ethyl acetoacetate. Both the N,N-syn and the N,N-anti products have been fully characterised by mass spectrometry and NMR analysis, and the regioselectivity of their formation is discussed in terms of solvent polarity and/or the nature of the metal ion. We demonstrate here that, among a wide series of polar and apolar solvents, tert-butyl alcohol is the best choice to enhance the yield of the N,N-syn regioisomer, while the N,N-anti regioisomer can be obtained with a very high selec-

Synthesis and In‐Vitro Cytotoxicity Evaluation of Novel Naphtindolizinedione Derivatives, Part II: Improved Activity for Aza‐Analogues

“…It is noteworthy that in the reaction using 2,3-dichloro-1,4-naphtoquinone, methylacetoacetate, and 3-methylpyridine, products 5a / 5b were formed in the ratio 72 : 28. This can be explained from the proposed cyclization mechanism, implying both C-and N-nucleophile attacks with displacement of chlorine atoms, followed by the ring closure [2,8]. The latter step can involve the 6-or 2-positions in 3-methylpyridine, leading to product 5a or 5b, respectively.…”

“…Methyl esters 5a / 5b, 6, 7 and 8, 9 are prepared starting from 2,3-dichloro-1,4-naphtoquinone or 6,7-dichloroquinoline-5,8-dione [2], respectively and suitable nucleophilic reagents through an one-pot cyclization assisted by microwave irradiation. The involvement of the preformed complex of 6,7-dichloroquinoline-5,8-dione with the eco-friendly salt MgCl 2 is able to induce a highly regio-selective production of the N,N-anti ester 9 [3], whereas the N,N-syn isomer 8 (Scheme 1) is obtained by the most convenient procedure (see Experimental, Section 4) selected among the series of experimental conditions previously investigated [2,3]. It is noteworthy that in the reaction using 2,3-dichloro-1,4-naphtoquinone, methylacetoacetate, and 3-methylpyridine, products 5a / 5b were formed in the ratio 72 : 28.…”

“…1 belong to this class of compounds. Recently, we have studied the multi-component cyclization to aza-derivatives 2 and 3 starting from 6,7-dichloroquinoline-5,8-dione showing that the regio-selective formation of the N,N-syn 2 and N,N-anti 3 isomers depends on solvent and metal-ion chelation effects [2]. Moreover, we have also successfully exploited microwave irradiation to gain the same heterocyclic products, which can be obtained more advantagously this way (higher yields, shorter reaction times, and lower formation of by-products) than using conventional heating [3].…”

Metal‐assisted regioselectivity in nucleophilic substitutions: a study by Raman spectroscopy and density functional theory calculations

“…Semi-empirical Zerner's Intermediate Neglect of Differential Overlap (ZINDO) calculations offered an appropriate tool to explain the regioselectivity observed with different metal ions. [5] We have now turned our attention on some metal complexes of the same reagent 6,7-dichloroquinoline-5,8-dione (1, Fig. 1), whose chelation property has been attributed to the involvement of N and O C(9) atoms.…”

“…[10] The structural characterization of the metal complexes by using Raman spectroscopy is rather unusual in the organic chemists community when compared to standard techniques such as nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESI MS), which were previously employed by us also. [5] The aim of this work is the study of a series of metal Arbitrary numbering according to Gaussian software for 1 and its complexes is used for convenience; numbering for 2 and 3 is in agreement with chemical nomenclature and was used only for describing NMR data in Experimental section.…”