Quinoline formation via a modified Combes reaction: examination of kinetics, substituent effects, and mechanistic pathways

Abstract

A comprehensive product regioselectivity and kinetics study of the modified Combes quinoline synthesis shown below has been undertaken: This is the first reported investigation of the Combes condensation employing 19F NMR spectroscopy to monitor intermediate consumption and product formation rates. The reaction was found to be first order in both the diketone and aniline. Product regioselectivity and reaction rates were found to be influenced by substituents on the diketones and anilines with rates varying as much as five fold. The consumption rate of key imine and enamine intermediates mirrored quinoline formation rates, in accord with rate determining annulation. A r of S0.32 was determined for this cyclization. While the sign of the reaction constant is consistent with rate limiting electrophilic aromatic substitution (EAS), the magnitude is likely a composite value, resulting from opposing substituent effects in the nucleophilic addition and EAS steps. Mechanistic details and reaction pathways supporting these findings are proposed. Copyright

Microwave Assisted Synthesis and Antimicrobial Potential of Quinoline‐Based 4‐Hydrazide‐Hydrazone Derivatives

“…They were purchased from Sigma Aldrich, USA and except for cyclopentanone and isatin which were purchased BDH Chemicals, UK, but were made Table 2 The minimum inhibitory concentration (MIC) test of hydrazide-hydrazones 4a-l (μg/mL). 6 , as solvent for sample preparation prior to analyses. In addition, DEPT-135 NMR analysis was also evaluated for all the synthesized compounds.…”

“…Due to wide application of quinoline core in many medicinal and industrial processes, various synthetic approaches have been used for the synthesis of this valuable heterocyclic system. These methods include the following: Pfitzinger approach which is reaction of isatin with ketones and aldehyde ; Doebner–Von Miller method, which is composed of reaction of an aniline with α,β‐unsaturated carbonyl compounds ; Conrad–Limpach method which is based on the condensation of anilines with β‐ketoesters ; Combe synthetic approach which involves the reaction of β‐diketones, with primary aryl amines like aniline and Friedlander synthetic approach which proceeded by the condensation of 2‐aminoaryl ketones with α‐methyleneketones . Another method which has become one of the most efficient processes for the synthesis of quinolines is Povarov synthetic approach which is an inverse electron demand aza‐Diels–Alder reaction of N ‐aryl imines, derived from aldehydes and anilines, with electron rich olefins and Skraup method .…”

Copper-Catalyzed Three-Component Synthesis of Quinolines via Oxidation and Aza-Diels-Alder Reaction

“…A variety of quinolines exhibit good biological activities, such as antihypertensive, anti-inflammatory, antimalarial and anticancer activities. [1] Recognizing the commercial significance of quinolines, the traditional preparation methods including Skraup synthesis, [2] Friedländer synthesis, [3] Doebner-von Miller reaction, [4] Combes synthesis [5] and Pavorov reaction [6] have been developed to construct quinoline skeletons over the past few decades. However, most of them suffer from some drawbacks, such as high temperature, strong acid, toxic starting reagents and harsh reaction conditions.…”

Ionic Liquid as an Efficient Medium for the Synthesis of Quinoline Derivatives via α-Chymotrypsin-Catalyzed Friedländer Condensation

“…In addition, quinoline derivatives are valuable synthons for the preparation of nano- and mesostructures with enhanced electronic and photonic properties [ 8 , 9 ]. Various methods were developed for the synthesis of this class of compounds, such as the Skraup synthesis [ 10 ], Doebner–Von Miller reaction [ 11 ], Combes synthesis [ 12 ], and the Friedländer method [ 13 ]. Among these, the Friedländer method, which involves a condensation reaction between a 2-aminoaryl ketone and a α-methylene ketone, is the most simple and straightforward.…”