Multi-component reactions (MCRs) are one of the most powerful and versatile tools for the construction of structurally complex and diverse organic compounds from simple and readily available starting materials because of their high efficiency in the cascade formation of several chemical bonds in a single operation ^{[1, 2, 3, 4, 5, 6]}. The multicomponent reactions in the library synthesis of structurally complex compounds and the evaluation of their biological activities still remains a continuing interest in chemical community.

The heterocycles,quinolines in particular,can be found in a wide variety of naturally occurring compounds,and many of them have been widely recognized as important subunits in the design of synthetic drug candidates due to their significant pharmacological properties as antimalarial ^{[7, 8]},antibacterial ^[9],anti-inflammatory ^[10],antituberculosis ^[11],anti-HIV ^{[12, 13]},anticancer agents ^[14], etc. Among the various quinoline derivatives,quinoline 2,4- dicarboxylates are of great interest due to their carboxyl groups play a pivotal role in the unique bioactivities of quinolines,and such functional groups provide an attractive venue for further structural elaboration ^{[15, 16, 17, 18]}. As a consequence of their unique chemical and biological properties,quinoline-2-carboxylates have been increasingly pursued. Generally,quinoline 2,4-dicarboxylates were prepared from a condensation reaction of dimethyl ketoglutaconate (DKG) with substituted anilines ^{[15, 16, 17, 18, 19, 20, 21]} or a selective conjugate reaction of the preformed N-arylphosphazenes with α,β-unsaturated carbonyl compounds ^[22]. Nevertheless,these methods usually suffer fromsomedrawbacks,suchas lowyield,a large amountof acid promoters needed,hardly available reactants,and the generation of stoichiometric amounts of wastes. Recently,Wang and co-workers ^[23] reported an iron-catalyzed three-component tandem reaction of aromatic amines,glyoxylic esters,and a-ketoesters leading to quinoline 2,4-dicarboxylates.However,thiswell-developedreaction require transitionmetal catalysts,whichmight thereby increase the risk for trace of toxic metals in the products,and limit their wide applications in the field of synthetic and pharmaceutical chemistry. Therefore,the development of simple,convenient,and environmentally benignmethods to construct quinoline-2,4-dicarboxylates still remains highly desirable.

Molecular iodine has attracted considerable attention in modern synthetic chemistry due to its charming advantages of cheapness,nontoxicity,water-tolerance and operation simplicity ^{[24, 25, 26, 27, 28]}. The mild Lewis acidity associated with iodine enhanced its usage in organic synthesis to realize various organic transformations ^{[29, 30, 31, 32, 33, 34]}. So the development of a reaction that employs catalytic amounts of readily available iodine should contribute to the creation of environmentally friendly processes. Herein,we wish to report an iodine-catalyzed three-component one-pot synthesis of quinoline-2,4-dicarboxylates from readily available aromatic amines,glyoxylic esters ^{[35, 36]},and a-ketoesters under mild and metal-free reaction conditions (Scheme 1).

Scheme. 1

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Scheme. 1.Iodine-catalyzed three-component one-pot synthesis of quinoline-2,4- dicarboxylates.

All commercially available,reagent grade chemicals were purchased from Alfa Aesar,Aldrich or Energy Chemical Company and used as received without further purification unless otherwise stated. All solvents were dried according to the standard procedures. ¹H NMR and ¹³C NMR were recorded in CDCl3 on a Bruker Avance III 400 spectrometer with TMS as an internal standard (400 MHz ¹H,100 MHz ¹³C) at room temperature,the chemical shifts (δ) were expressed in ppm and J values were given in Hz. Mass analyses and HRMS were obtained on a Finnigan- LCQDECA mass spectrometer and a Bruker Daltonics Bio-TOF-Q mass spectrometer by the ESI method,respectively. Column chromatography was performed on silica gel (200-300 mesh).

To a mixture of arylamine 1 (0.5 mmol),ethyl glyoxylate 2 (0.6 mmol),a-ketoester 3 (0.75 mmol),and I₂ (5 mol%) in a 25 mL round-bottomed flask at room temperature,was added CH3CN (2 mL). The reaction mixture was allowed to stir at room temperature or 60 ℃ for 24-32 h. After the reaction,the solvent was then removed under vacuum. The residue was purified by flash column chromatography using a mixture of petroleum ether and ethyl acetate as eluent to give the desired products.

Initially,the reaction conditions were optimized using commercially available p-toluidine (1a),ethyl glyoxalate (2a,50 wt% solution in toluene),and methyl pyruvate 3a as starting materials in the presence of 5 mol% of molecular iodine under air. As shown in Table 1,the screening of reaction media found that solvents played an important role in this transformation. The highest yield of 75% was obtained in MeCN at room temperature (Table 1,entry 4). When the reaction was performed in THF,DME,1,4-dioxane, toluene,or CH₂Cl₂,respectively,the yields were slightly inferior to the results in MeCN (Table 1,entries 1-6). The reactions in DMSO and MeOH only afforded the desired product 4a in 24% and 9% yields,respectively (Table 1,entries 7 and 8). The effects of catalyst loading were also examined and 5 mol% of iodine was found to be the best choice. Reducing or increasing the amount of iodine gave lower yields (Table 1,entries 9-11). No conversion was observed in the absence of catalyst (Table 1,entry 12). It indicates that molecular iodine played a key role in the formation of quinoline-2,4-dicarboxylate 4a. The appropriate proportion of the p-toluidine 1a,ethyl glyoxalate 2a,and methyl pyruvate 3a was 1:1.2:1.5 (Table 1,entries 4,13,and 14).

Table 1

Table 1 Reaction of p-anisidine 1a, ethyl glyoxylate 2a, and methyl pyruvate 3a under various reaction conditions.a

Table 1 Reaction of p-anisidine 1a, ethyl glyoxylate 2a, and methyl pyruvate 3a under various reaction conditions.a

Under the optimized conditions,the scope of the iodinecatalyzed three-component reaction was investigated and the results are shown in Fig. 1. Generally,both electron-rich and electron-deficient aromatic amines were suitable for this process, giving the corresponding products in moderate to good yields (4a- 4m). It should be noted that aromatic amines bearing alkoxy and aryloxy groups could be used in the reaction to give the expected products 4b-4e. Long chain alkyl substituted aromatic amine such as 4-butylaniline could also be transformed into the desired product in good yields (4f). Notably,a variety of functional groups such as amino,halogen,trifluoromethyl,carbonyl,and cyano groups were all well tolerated in this process,whose corresponding products 4g-4m can be further modified. In addition,ethyl 2- oxopropanoate and (2S,5R)-2-isopropyl-5-methylcyclohexyl 2- oxoacetate in our cases could also be used in this transformation, and the desired products (4n and 4o) were obtained in good yields.

Fig. 1

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Fig. 1.Results for molecular iodine catalyzed one-pot synthesis of quinoline-2,4-carboxylates. What in parenthesis are isolated yields based on 1. a Reaction conditions are at 60 ℃ for 32 h.

It is known that Lewis acid (FeCl₃) can catalyze threecomponent tandemreactions of aromatic amines,glyoxylic esters, and a-ketoesters leading to quinoline-2,4-dicarboxylates ^[23]. We inferred that the present cascade reaction catalyzed by iodine was similar to the process of iron-catalyzed cascade reaction for the construction of quinoline-2,4-dicarboxylates proposed by Wang and co-workers ^[23]. As shown in Scheme 2, Firstly,aromatic amine 1 reacted with ethyl glyoxylate 2 to give the imine 5,which was followed by the addition of the enolate 3' that quickly formed from the tautomerization of ketoester in the presence of molecular iodine,to generate intermediate 6 ^[37]. Subsequently,the nucleophilic attack of the phenyl ring to the keto group produced intermediate 7. Next,the elimination of water and the following proton transfer would generate the 1,2-dihydroquinoline intermediate 8. Finally,the intermediate 8 was oxidized by air oxygen to give the desired product 4 ^{[23, 37]}. The present cascade reaction pathway involving an imine intermediate could be confirmed by the following two control experiments. Accordingly,when the reaction of pmethoxyaniline 1b with ethyl glyoxylate 2a was performed in the absence of molecular iodine and methyl pyruvate,imine 5b was obtained in 86% yield (Scheme 3). Furthermore,the desired product 4bwas isolated in 68% yieldwhen the reaction of imine 5b with methyl pyruvate 3a was conducted using the standard procedure (Scheme 4). The above results suggested that imine complex should be the key intermediate in the present reaction system.

Scheme. 2

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Scheme. 2.Possible reaction mechanism.

Scheme. 3

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Scheme. 3.The reaction of p-methoxyaniline 1b with ethyl glyoxylate 2a.

Scheme. 4

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Scheme. 4.The reaction of imine 5b with methyl pyruvate 3a in the presence of molecular iodine.

In summary,we have developed a metal-free procedure for the synthesis of quinoline-2,4-carboxylates through a molecular iodine-catalyzed three-component tandem reaction of arylamines, ethyl glyoxylate,and α-ketoesters. A series of biologically important quinoline-2,4-carboxylates could be conveniently and efficiently obtained in moderate to good yields from readily available starting materials with excellent functional group tolerance. This simple and metal-free reaction system is expected to extend the potential applications of quinoline-2,4-carboxylates in the synthetic and pharmaceutical chemistry. Further investigations of reaction scope,precise mechanism,and the synthetic applications are ongoing.

The work was financially supported by the Opening Project of Key Laboratory at Universities of Education Department of Xinjiang Uygur Autonomous Region (No. 2014YSHXZD01).