Based On The Metal-free Catalytic Quinoline Nitrogen Oxide Ortho-CH Bond Olefination Reaction

Quinoline and its derivatives are an important class of heterocyclic compounds which widely exist in nature. Due to their diverse chemical properties, a variety of quinoline derivatives can be obtained and they have found widespread use in pharmaceutical industry, dye chemistry and molecular biology. In particular, C2-olefination quinolones, the key component forming pharmaceutical or potentional pharmaceutical molecules play a crucial role in bioactive molecules, such as Montelukast, Chimanine B, and VUF 5017. As a result, selective alkenylation at C2-position of quinolines is great significant in organic synthesis and relatively much attention had been paid to this motifs.Representative methods for the synthesis of 2-alkenylquinoline derivatives include Witting reaction using 2-quinolinecarboxaldehyde as substrate, reaction of 2-methylquinoline with aldehyde or imine, coupling reaction of quinoline N-oxides with alkenyl boronic acid and transition metal-catalyzed coupling reaction of quinoline N-oxides with olefines. Despite these elegant approaches, the currently available methods have some shortcomings. For example, substitutied 2-methylquinolines or 2-quinolinecarboxaldehyde employed as an necessary partner in these strategies are not commercial available and problematic to prepare from other material. In addition, Pd and other noble metal catalysts would increase the cost. Therefore, the exploration of more efficient, widely applicable and greener methods is in great need. To this end, we found a new method to attain 2-alkenylquinoline by directly ortho C-H bond olefination of quinoline N-oxides under metal-free conditions.Firstly, we studied the reaction by using the quinoline N-oxide and ethyl acrylate as template substrate to screen the reaction conditions of solvents, additives, reaction temperature, reaction time and the ratio of substrates, and found the optimum conditions as follows:using AcOH (3 equiv) as an additive in DMSO at 120? for 40 hours, and the starting material ratio of quinoline N-oxide and acrylic ester was 1:10. Under the optimum conditions, the effect of acrylate on the ortho C-H bond olefination was investigated. The results showed that the yield decreased with the increase of steric hindrance of the acrylate compound (from 44% to 63%). For the similar reason, the ?-or ?-methyl substituted methyl acrylate could not react with quinoline N-oxide under the optimum conditionsNext, with the optimum conditions in hand, we we explored a series of acrylic esters different quinoline N-oxides. It was found that different substituted quinoline N-oxides reacted well and both electron-donating groups (-Me, OMe) or electron-withdrawing groups (Br, Cl, F,-OH,-NO2,-CO2Me) substituted quinoline N-oxides could successfully transform to corresponding products in 29%-82% yields.Subsequently, we investigated the reaction with different styrenes. The results showed that substitution at ortho-, meta- or para-position of the styrenes with either electron-rich or electron-withdrawing groups were well tolerated under the optimized conditions, and the yields could up to 80%. In addition, we explored some other olefinic derivatives such as ethyl vinyl ketone, acrylamide, acrylic acid, allyl alcohol, acrolein, dimethyl vinylphosphosphonate and n-butyl vinyl ether under the same conditions. Among them only ethyl vinyl ketone could react with quinoline N-oxide and gave 65% yield of the target product.Then, the method was used to prepare (E)-methyl 3-(3-bromoquinolin-2-yl)acrylate (3gb) on grams scales by the reaction of 3-bromo quinoline N-oxide with methyl acrylate and obtaine 75% yield. Furthermore, a sequential one-pot two-steps process involving in-situ oxidation of quinoline followed by olefination with styrene was explored to synthesize (E)-2-styrylquinoline 5aa. This method greatly simplified the experimental operation and provided convenience for the large scale synthesis 2-alkenylquinolines.Finally, based on the free radical capture experiment and intermediate control experiment, a possible mechanism was proposed, which involved a sequential 1,3-dipolar cycloaddition and AcOH assisted ring opening step followed by dehydration and rearomatization to target product.