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Recent Advances in Metal-Free Quinoline Synthesis

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Recent Advances in Metal-Free Quinoline Synthesis molecules Review Recent Advances in Metal-Free Quinoline Synthesis Ginelle A. Ramann and Bryan J. Cowen * Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80208, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-303-871-2981; Fax: +1-303-871-2254 Academic Editor: Wim Dehaen Received: 27 June 2016; Accepted: 22 July 2016; Published: 29 July 2016 Abstract: The quinoline ring system is one of the most ubiquitous heterocycles in the fields of medicinal and industrial chemistry, forming the scaffold for compounds of great significance. These include anti-inflammatory and antitumor agents, the antimalarial drugs quinine and chloroquine, and organic light-emitting diodes. Quinolines were first synthesized in 1879, and since then a multitude of synthetic routes have been developed. Many of these methods, such as the Skraup, Doebner–Von Miller, and Friedlander quinoline syntheses, are well-known but suffer from inefficiency, harsh reaction conditions, and toxic reagents. This review focuses on recent transition metal-free processes toward these important heterocycles, including both novel routes and modifications to established methods. For example, variations on the Skraup method include microwave irradiation, ionic liquid media, and novel annulation partners, all of which have shown increased reaction efficiency and improved yield of the heteroring-unsubstituted quinoline products. Similarly, modifications to other synthetic routes have been implemented, with the quinoline products displaying a wide variety of substitution patterns. Keywords: quinoline; heterocycle; metal-free 1. Introduction Quinoline was discovered by Runge in 1834 as one of the many components extracted from coal tar [1]. While this nitrogen-based heterocycle is not overly useful in and of itself, it is easily modified with simple to complex functionalities, giving a multitude of compounds that are ubiquitous in the fields of medicinal and industrial chemistry. Prominently, the first and most widely used antimalarial agent, quinine (I, Figure1), contains the quinoline scaffold, as do the closely related derivatives chloroquine (II) and mefloquine (III)[2]. Several promising anti-inflammatory and antitumor therapeutics are also built on this structure. Alternatively, quinolines provide frameworks for industrial uses including organic light-emitting diodes (OLEDs) and photovoltaic cells, as well as solvents for terpenes and resins. In addition, quinoline-based dyes such as ethyl red iodide (IV) and pinacyanol (V) have been used since the beginning of the nineteenth century in photographic plates [3]. The prevalence of the quinoline ring system in a vast range of medical and industrial settings can be ascribed mainly to its versatility and broad potential for functionalization. In fact, it is this versatility which earned it the designation of “privileged scaffold” in medicinal chemistry, a term coined by Evans in 1988 which refers to simple structural subunits present in diverse therapeutic compounds with distinctive receptor affinities [4]. Consequently, the synthesis of variously substituted quinolines has been a recurring endeavor for nearly a century and a half [5]. A multitude of synthetic methods have been established over this timeframe, which construct the quinoline ring from diverse starting materials and result in products with nearly limitless combinations of functionality. Molecules 2016, 21, 986; doi:10.3390/molecules21080986 www.mdpi.com/journal/molecules Molecules 2016, 21, 986 2 of 23 Molecules 2016, 21, 986 2 of 22 Molecules 2016, 21, 986 N 2 of 22 N HO H N HO N N MeO H N HO H HO N Cl N N NCF3 MeO CF H I II3 III N Cl N N CF N 3 CF3 + I II+ III N - N - N I Cl IV N V + + N - N - N FigureFigure 1. Structures 1. Structures of quinine ofI quinine(I), chloroquine (I); chloroquine (II), mefloquine (II); ( mefloquineIIICl ), ethyl red ( IIIiodide); ethyl (IV), redand pinacyanol iodide (IV ();V). and pinacyanol (V). IV V 2. Established Methods of Quinoline Synthesis Figure 1. Structures of quinine (I), chloroquine (II), mefloquine (III), ethyl red iodide (IV), and pinacyanol (V). 2. EstablishedMany methods Methods have of been Quinoline instituted Synthesis to react aniline with various annulation partners to obtain 2.quinolines. EstablishedMany methods One Methods of the have oldest of been Quinoline and instituted most enduring Synthesis to react of anilinesuch procedures with various is the annulationSkraup reaction partners (A, Figure to obtain 2). In 1880, Czech chemist Zdenko Hans Skraup heated aniline and glycerol with an oxidant in concentrated quinolines. One of the oldest and most enduring of such procedures is the Skraup reaction sulfuricMany acid, methods a method have that been is institutedstill commonly to react used ani forline the with production various annulation of heteroring-unsubstituted partners to obtain (A, Figure2 ). In 1880, Czech chemist Zdenko Hans Skraup heated aniline and glycerol with an quinolines.quinolines [6].One The of the Doebner oldest andmethod most (B), enduring introduced of such by proceduresOscar Doebner is the in Skraup 1887, combines reaction (A, aniline Figure with 2). oxidant in concentrated sulfuric acid, a method that is still commonly used for the production of Inan 1880, aldehyde Czech and chemist pyruvic Zdenko acid to Hans give 2-substitutedSkraup heated quinoline-4-carboxylic aniline and glycerol with acids. an A oxidant variation in ofconcentrated the Skraup heteroring-unsubstituted quinolines [6]. The Doebner method (B), introduced by Oscar Doebner in sulfuricprocedure, acid, the a Doebner–Vonmethod that is Miller still commonly reaction (C) used was for introduced the production in 1881 of andheteroring-unsubstituted uses α,β-unsaturated 1887,quinolinesaldehydes combines or[6]. anilineketones The Doebner withto obtain an method aldehyde 2- and (B), 4-substituted andintroduced pyruvic quinolinesby acid Oscar to giveDoebner under 2-substituted acidic in 1887, conditions. combines quinoline-4-carboxylic The aniline Conrad– with acids.anLimpach aldehyde A variation reaction and pyruvic of (D), the reported Skraupacid to givein procedure, 1887, 2-substituted is also the conducted Doebner–Vonquinoline-4-carboxylic by refluxing Miller in reactionacids. acid, A but variation (C) uses was β -ketoestersof introduced the Skraup as in 1881procedure,the and annulation uses theα, βpartnerDoebner–Von-unsaturated to give Miller aldehydes2- and reaction3-substituted or ketones(C) was quinolin-4-ols to introduced obtain 2- [7]. andin As1881 4-substituted a contemporaryand uses α quinolines,β-unsaturated example, under in acidicaldehydes1963 conditions. L.S. Povarov or ketones The and Conrad–Limpach tocoworkers obtain 2- reacted and 4-substituted reactionaryl aldehyde (D), quinolines reporteds and activated under in 1887, alkenesacidic is also conditions. to conductedform 2-arylquinolines The by Conrad– refluxing inLimpach acid,(E) [8]. but reaction uses β-ketoesters (D), reported as in the 1887, annulation is also conducted partner to by give refluxing 2- and in 3-substituted acid, but uses quinolin-4-ols β-ketoesters as [ 7]. Asthe a contemporary annulation partner example, to give in 19632- and L.S. 3-substituted PovarovA. and quinolin-4-ols coworkers reacted[7]. As a aryl contemporary aldehydes example, and activated in alkenes1963 L.S. to formPovarov 2-arylquinolines and coworkers (E)reacted [8]. aryl aldehydeSkraup s and activated alkenes to form 2-arylquinolines N (E) [8]. A. Skraup E. 2 B. HO N O Povarov N Doebner h P NAr , NR HO 4 O S 2 E. 2 B. O Ar- HO H Povarov CH N HO Doebner O h , B -C F P R O O NAr 3 O , NROH O E 4 HOt NH HO O 2 S 2 A H r-C HO OO HO H , B -C Δ F R O O OH O , 3 OE H + 4 t SO NH2 HO H 2 NR R O NR 1 2 O 1 R O R 3 1 R Δ 2 H + R2 , SO 4O O 2 R R OH H 1 O 2 NR1 R2 NR1 D. R3O R1 C. R2 Conrad-LimpachR Doebner-Von Miller 2 O O R OH 1 R2 Figure 2. Quinoline synthesis methods: Skraup reaction (A); Doebner reaction (B); Doebner–Von D. C. Miller reactionConrad-Limpach (C); Conrad–Limpach reaction (D); and Povarov reactionDoebner-Von (E). Miller FigureFigureAlternatively, 2. Quinoline2. Quinoline several synthesis synthesis other methods: estab methods:lished Skraup Skraup methods reaction reaction of quinol (A );(A Doebner);ine Doebner synthesis reaction reaction utilize (B); ( Doebner–VonB su); bstratesDoebner–Von other Miller than anilinereactionMiller in the (reactionC );cyclization Conrad–Limpach (C); Conrad–Limpach process. reactionThe Friedländer reaction (D); and (D Povarovreac); andtion Povarov reaction(F, Figure reaction (E 3),). reported (E). by Paul Friedländer in Alternatively, several other established methods of quinoline synthesis utilize substrates other than aniline in the cyclization process. The Friedländer reaction (F, Figure 3), reported by Paul Friedländer in Molecules 2016, 21, 986 3 of 23 Alternatively, several other established methods of quinoline synthesis utilize substrates other than aniline in the cyclization process. The Friedländer reaction (F, Figure3), reported by Paul FriedländerMolecules 2016 in 1882,, 21, 986uses 2-aminobenzaldehyde with another carbonyl component to form3 of 222- and 3-substituted quinolines. Similarly, the Pfitzinger (G) reaction combines isatin with a carbonyl 1882, uses 2-aminobenzaldehyde with another carbonyl component to form 2- and 3-substituted compound under basic conditions to give 2- and 3-substituted quinoline-4-carboxylic acids [9]. quinolines. Similarly, the Pfitzinger (G) reaction combines isatin with a carbonyl compound under Whilebasic not conditions an exhaustive to give list, 2- and these 3-substituted examples quino highlightline-4-carboxylic the breadth acids of[9]. options While not in an the exhaustive formation of quinolinelist, these ring examples systems. highlight the breadth of options in the formation of quinoline ring systems. R 1 R NH2 2 NR1 O R2 O F. Friedlander R O 1 R 2 NR O 1 O N R2 H O OH G. Pfitzinger FigureFigure 3. Quinoline 3. Quinoline synthesis synthesis methods: methods: Friedländer reaction reaction (F); (F and); and Pfitzinger Pfitzinger reaction reaction (G).
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