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

NAr , NR HO 4

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

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

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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). (G).

In general, these methods are powerful tools in the synthesis of a broad range of quinolones-from Inunsubstituted general, these to highly methods functionalized. are powerful However, tools innone the of synthesis the methods of adescribed broad range thus far of are quinolones-from without unsubstituteddrawbacks. to Many highly suffer functionalized. from low efficiency, However, harsh none reagents of the and methods reaction describedconditions, thusand functional far are without drawbacks.group incompatibility. Many suffer from Therefore, low efficiency,the quest to harsh modify reagents these reactions and reaction to addres conditions,s their inherent and issues functional grouphas incompatibility. been a recurring Therefore, endeavor of the numerous quest to research modify groups. these reactions to address their inherent issues has been aThis recurring review documents endeavor recent of numerous progress in research quinoline groups. synthesis, particularly in the area of transition metal-free methods. While transition metal catalysis has been a popular field of late, those reactions This review documents recent progress in quinoline synthesis, particularly in the area of transition are outside the scope of the current paper and will not be covered. metal-freeThe methods. review is While organized transition into two metal main catalysissections. First, has beenestablished a popular procedures field ofwill late, be addressed, those reactions are outsidehighlighting the scope the problems of the current unique paperto the individual and will notprocedures be covered. and detailing modifications in recent Theliterature. review Then is organized novel reaction into schemes two main willsections. be explored First, and establishedcompared to proceduresprevious examples. will be addressed, highlighting the problems unique to the individual procedures and detailing modifications in recent literature.3. Quinoline Then novel Synthesis reaction via Modifications schemes will to be Aniline-Based explored and Established compared Methods to previous examples.

3. Quinoline3.1. Skraup Synthesis Reaction via Modifications to Aniline-Based Established Methods As previously mentioned, the Skraup reaction is one of the oldest methods of quinoline synthesis 3.1. Skraupand is Reactionstill widely employed in the formation of heteroring-unsubstituted quinolines. However, the conventional reaction outlined by Skraup, in which aniline and glycerol are refluxed with an oxidant As previously mentioned, the Skraup reaction is one of the oldest methods of quinoline synthesis for an extended period of time in concentrated sulfuric acid, ubiquitously results in a thick tar from and iswhich still widely the crude employed product is indifficult the formation to extract. ofTh heteroring-unsubstitutede harsh reaction conditions, toxic quinolines. reagents, However,and low the conventionalyield of product reaction do outlined not recommend by Skraup, this procedure in which fo aniliner practical and application. glycerol are Nonetheless, refluxed witha dearth an of oxidant for anprocedures extended that period are applicable of time in to concentrated formation of he sulfuricteroring-unsubstituted acid, ubiquitously quinolines results exist, in compelling a thick tar from whichseveral the crude groups product to modify is difficult the reaction to extract. conditions The to harshmitigate reaction these inherent conditions, flaws. toxic reagents, and low yield of productThe use doof microwave not recommend irradiation this in procedure place of conv forentional practical heat application. sources has become Nonetheless, popular aover dearth of proceduresthe last that decade. are applicableCristea et al. to [10] formation found microwave of heteroring-unsubstituted irradiation to be an effi quinolinescient heat source exist, for compelling the synthesis of quinolines, reducing the required reaction time and increasing yield. However, their several groups to modify the reaction conditions to mitigate these inherent flaws. continued use of arsenic pentoxide as oxidizing agent did not ameliorate the harsh reaction conditions Thecommon use ofto this microwave method. Drawing irradiation on this in work, place Am ofarasekara conventional and Hasan heat [11] sources also applied has becomemicrowave popular over theheating last to decade.the Skraup synt Cristeahesis, etreacting al. [10 anilines] found 1 with microwave glycerol 2 in irradiation a 1:3 ratio (Figure to be 4). anDivergently, efficient heat sourcereplacement for the synthesis of the concentrated of quinolines, sulfuric reducing acid with thean imidazolium required reaction cation-based time sulfonic and increasing acid ionic yield. However,liquid their 3a significantly continued improved use of arsenic the reaction pentoxide outcome; as it oxidizingwas also noted agent that did addition notameliorate of an exogenous the harsh reactionoxidant conditions was unnecessary. common toUsing this these method. modifi Drawingcations, they on thisobtained work, quinoline Amarasekara product and4 in Hasanvery [11] also appliedgood yields. microwave heating to the Skraup synthesis, reacting anilines 1 with glycerol 2 in a 1:3 ratio (Figure4). Divergently, replacement of the concentrated sulfuric acid with an imidazolium cation-based sulfonic acid ionic liquid 3a significantly improved the reaction outcome; it was also Molecules 2016, 21, 986 4 of 23 noted that addition of an exogenous oxidant was unnecessary. Using these modifications, they obtained quinolineMolecules product 2016, 21, 4986in very good yields. 4 of 22

Molecules 2016, 21, 986 4 of 22 Molecules 2016, 21, 986 4 of 22

Figure 4. Skraup reaction in ionic liquid medium under microwave irradiation. Figure 4. Skraup reaction in ionic liquid medium under microwave irradiation. Figure 4. Skraup reaction in ionic liquid medium under microwave irradiation. Concurrently—and also citing Cristea and coworkers as foundational—Len et al. [12] applied Concurrently—andFigure 4. Skraup also citing reaction Cristea in ionic and liquid coworkers medium under as foundational—Len microwave irradiation. et al. [12] applied microwaveConcurrently—and heating to quinoline also citing synthesis Cristea andwithin cowork theirers laboratory as foundational—Len′s theme of “green et al. [12] chemistry” applied microwave heating to quinoline synthesis within their laboratory1s theme of “green chemistry” microwavetechniques.Concurrently—and Omittingheating to the quinolinealso exogenous citing synthesis Cristea oxidan tand withinand cowork heating theirers monosubstitutedlaboratory as foundational—Len′s theme anilines of “green et1 withal. [12]chemistry” glycerol applied 2 techniques.microwavetechniques.in concentrated Omitting heatingOmitting sulfuric theto the quinoline exogenous acidexogenous under synthesis oxidant200oxidan °C tmicrowave withinand and heating heating their irradiation, monosubstitutedlaboratory monosubstituted they′s theme obtained anilines of anilines “green a 1 widewith 1 chemistry”glycerolvarietywith glycerol of 2 ˝ 2 intechniques. concentratedinmono-functionalized concentrated Omitting sulfuric sulfuric the quinoline acidacidexogenous under under analogs oxidan200 200 °C5 Ctinmicrowave and microwavefair heating to good irradiation, monosubstituted irradiation, yield (Figure they theyobtained 5).anilines obtainedThey a 1widealso with anotedvariety glycerol wide the varietyof 2 essentiality of sulfuric acid as catalyst and the improved extraction efficacy with the addition of water of mono-functionalizedinmono-functionalized concentrated sulfuric quinoline acid under analogs analogs 200 °C5 5inmicrowavein fair fair to togood irradiation, good yield yield (Figure they (Figure obtained 5). 5They). They a alsowide also noted variety noted the of the to the reaction mixture as solvent. essentialitymono-functionalizedessentiality of sulfuric of sulfuric acid quinoline acid as as catalyst catalyst analogs and and the5the in improvedimpr fairoved to good extraction extraction yield efficacy(Figure efﬁcacy with 5). with theThey theaddition also addition noted of water ofthe water to theessentialityto reaction the reaction of mixture sulfuric mixture as acid solvent.as solvent.as catalyst and the improved extraction efficacy with the addition of water to the reaction mixture as solvent.

Figure 5. Skraup reaction under microwave irradiation. Figure 5. Skraup reaction under microwave irradiation. Shteingarts and coworkersFigure 5. Skraup [13] found reaction an underintere microwavesting divergence irradiation. of reactivity during their Figure 5. Skraup reaction under microwave irradiation. investigationShteingarts of biologically-relevantand coworkers [13] polyfluorinated found an intere heterocycles.sting divergence Refluxing of reactivity1,4,5,6,8-pentafluoro-2- during their Shteingartsinvestigationnaphthylamine of and 6biologically-relevant with coworkers glycerol 2 [in13 H] polyfluorinated2 foundSO4, this an group interesting heterocycles.expected divergenceto see Refluxing cyclization of1,4,5,6,8-pentafluoro-2- reactivityat the unsubstituted during their Shteingarts and coworkers [13] found an interesting divergence of reactivity during their investigationnaphthylamineortho position. of biologically-relevant However, 6 with glycerol to their 2 insurprise H polyfluorinated2SO4 ,they this groupisolated expected heterocycles. only the to polyfluorinated see cy Refluxingclization atbenzo[ 1,4,5,6,8-pentafluoro-2- the unsubstitutedf]quinoline, a investigationproduct of electrophilic of biologically-relevant substitution ofpolyfluorinated fluorine in the 1-positionheterocycles. (Figure Refluxing 6). The 1,4,5,6,8-pentafluoro-2- proposed mechanism naphthylamineortho position.6 with However, glycerol to their2 in surprise H2SO4, they this isolated group expected only the polyfluorinated to see cyclization benzo[ at thef]quinoline, unsubstituted a naphthylamine 6 with glycerol 2 in H2SO4, this group expected to see cyclization at the unsubstituted orthoproductforposition. this annulation of electrophilic However, begins tosubstitution theirwith the surprise conjugate of fluorine they addition in isolated the 1-position of onlynaphthylamine the (Figure polyfluorinated 6). to The acrolein proposed 7, benzo[ the mechanism productf ]quinoline, of orthoglycerol position. dehydration However, and to theirgenerally surprise presumed they isolated to be theonly active the polyfluorinated annulation partner benzo[ inf ]quinoline,the Skraup a a productfor this of annulation electrophilic begins substitution with the conjugate of fluorine addition in the of 1-position naphthylamine (Figure to6 ).acrolein The proposed 7, the product mechanism of productreaction of [6]. electrophilic Cyclization substitution then occurs ofthrough fluorine attack in the of 1-position the aromatic (Figure ring on6). Thethe carbonyl proposed group. mechanism Then for thisglycerol annulation dehydration begins and with generally the conjugate presumed addition to be the of active naphthylamine annulation topartner acrolein in the7, theSkraup product forafter this tautomerization annulation begins and with loss ofthe HF, conjugate the ring addition is rearomatized, of naphthylamine forming the to observed acrolein 7product, the product 8b. of of glycerolreaction dehydration [6]. Cyclization and then generally occurs through presumed attack to of bethe the aromatic active ring annulation on the carbonyl partner group. in the Then Skraup glycerolafter tautomerization dehydration and lossgenerally of HF, presumedthe ring is rearomatized,to be the active forming annulation the observed partner product in the 8bSkraup. reactionreaction [6]. [6]. Cyclization Cyclization then occurs occurs through through attack attack of the of aromatic the aromatic ring on ring the carbonyl on the carbonylgroup. Then group. Thenafter after tautomerization tautomerization and and loss lossof HF, of the HF, ring the is ring rearomatized, is rearomatized, forming forming the observed the observed product product8b. 8b.

Figure 6. Electrophilic substitution of fluorine in the Skraup reaction. Figure 6. Electrophilic substitution of fluorine in the Skraup reaction.

Figure 6. Electrophilic substitution of fluorine in the Skraup reaction. Figure 6. Electrophilic substitution of ﬂuorine in the Skraup reaction.

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3.2. DoebnerMolecules 2016 Reaction, 21, 986 5 of 22

MoleculesThe3.2. Doebner Doebner 2016, 21Reaction, 986 reaction, while not as well-known as the Skraup, is another method of5 of forming 22 quinoline rings from simple starting materials. The general procedure, combining aniline with The Doebner reaction, while not as well-known as the Skraup, is another method of forming benzaldehyde3.2. Doebner and Reaction pyruvic acid to form 2-substituted quinoline-4-carboxylic acids, typically suffers quinoline rings from simple starting materials. The general procedure, combining aniline with from lowThe yields Doebner or long reaction, reaction while times. not as Even well-known previous as examples the Skraup, of is modified another proceduresmethod of forming require the benzaldehyde and pyruvic acid to form 2-substituted quinoline-4-carboxylic acids, typically suffers quinoline rings from simple starting materials. The general procedure, combining aniline with use offrom harsh low reaction yields or conditions, long reaction large times. amounts Even prev ofious organic examples solvent, of modified or special procedures apparatus require [14]. the benzaldehyde and pyruvic acid to form 2-substituted quinoline-4-carboxylic acids, typically suffers Guouse of et harsh al. [ 15reaction] approached conditions, quinoline large amounts synthesis of organic via asolvent, Doebner-like or special process, apparatus in [14]. which they first from low yields or long reaction times. Even previous examples of modified procedures require the condensedGuo aniline et al. 1[15]with approached an aldehyde quinoline9 (Figure synthesis7). In contrastvia a Doebner-like to the typical process, method, in which they they replaced first the use of harsh reaction conditions, large amounts of organic solvent, or special apparatus [14]. pyruviccondensed acid component aniline 1 with with an aaldehyde second molecule9 (Figure 7). of In aldehyde, contrast to thus the typical obtaining method, quinolines they replaced substituted the at Guo et al. [15] approached quinoline synthesis via a Doebner-like process, in which they first the 2-pyruvic and 3-positions. acid component Moreover, with a second they foundmolecule that of aldehyde, addition thus of a obtaining substoichiometric quinolines substituted amount of at H O , condensed aniline 1 with an aldehyde 9 (Figure 7). In contrast to the typical method, they replaced the 2 2 the 2- and 3-positions. Moreover, they found that addition of a substoichiometric amount of H2O2, actingpyruvic as an acid environmentally-friendly component with a second oxidant molecule alternative, of aldehyde, increased thus obtaining the yield quinolines of quinoline substituted product, at as acting as an environmentally-friendly oxidant alternative, increased the yield of quinoline product, as did additionthe 2- and of 3-positions. a catalytic Moreover, amount of they aluminum found that chloride. addition The of proposeda substoichiometric mechanism amount of this of annulationH2O2, did addition of a catalytic amount of aluminum chloride. The proposed mechanism of this annulation beginsacting with as the an AlClenvironmentally-friendly3-mediated condensation oxidant ofaltern theative, aniline increased with one the moleculeyield of quinoline of aldehyde product, to giveas the begins with the AlCl3-mediated condensation of the aniline with one molecule of aldehyde to give imine.did The addition enol tautomerof a catalytic of amount a second of moleculealuminum of chloride aldehyde. The ( 9aproposed) then adds mechanism to the of imine, this annulation which cyclizes the imine. The enol tautomer of a second molecule of aldehyde (9a) then adds to the imine, which to givebegins the with tetrahydroquinoline. the AlCl3-mediated Loss condensation of one equivalent of the aniline of with H O one gives molecule the dihydroquinoline, of aldehyde to give which cyclizes to give the tetrahydroquinoline. Loss of one equivalent2 of H2O gives the dihydroquinoline, the imine. The enol tautomer of a second molecule of aldehyde (9a) then adds to the imine, which thenwhich aromatizes then aromatizes under hydrogen under hydrogen peroxide peroxide oxidation oxidation to give to the give final the final product. product. cyclizes to give the tetrahydroquinoline. Loss of one equivalent of H2O gives the dihydroquinoline, which then aromatizes under hydrogen peroxide oxidation to give the final product.

Figure 7. Doebner reaction using hydrogen peroxide as oxidant with Lewis acid catalyst. Figure 7. Doebner reaction using hydrogen peroxide as oxidant with Lewis acid catalyst. BharateFigure and 7. Vishwakarma Doebner reaction [16] using also reportedhydrogen a peroxide method as toward oxidant 2,3-disubstituted with Lewis acid catalyst. and 3-substituted Bharatequinolines and using Vishwakarma anilines and aldehydes [16] also reported(Figure 8). aDr methodawing on toward previous 2,3-disubstituted work by Yan et al., and which 3-substituted used Bharate and Vishwakarma [16] also reported a method toward 2,3-disubstituted and 3-substituted quinolinescopper(I) using bromide anilines and and trifluoromethanesulfonic aldehydes (Figure8 ).acid Drawing in DMSO on in previous the formation work byof these Yan etheterocycles, al., which used quinolines using anilines and aldehydes (Figure 8). Drawing on previous work by Yan et al., which used copper(I)they found bromide that andomission triﬂuoromethanesulfonic of the transition metal and acid replacement in DMSO of in the the acid formation and solvent of these with heterocycles,an ionic copper(I) bromide and trifluoromethanesulfonic acid in DMSO in the formation of these heterocycles, liquid ([Bmim]BF4, 3b) gave comparable yields of the two products in their model reaction. theythey found found that that omission omission of of the the transition transition metalmetal and replacement replacement of ofthe the acid acid and and solvent solvent with withan ionic an ionic liquidliquid ([Bmim]BF ([Bmim]BF4, 3b4, 3b) gave) gave comparable comparable yields yields of of the the two two products products in their in their model model reaction. reaction.

Figure 8. Divergent reactivity in the Doebner reaction in ionic liquid medium.

Figure 8. Divergent reactivity in the Doebner reaction in ionic liquid medium. Figure 8. Divergent reactivity in the Doebner reaction in ionic liquid medium.

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Interestingly, investigations investigations into into the the scope scope of the of reaction the reaction indicated indicated that the that ratio the of mono-to- ratio of mono-to-disubstituteddisubstituted product was product a direct was result a direct of both result reac oftion both time reaction and the time nature and the of the nature aldehyde of the substrate. aldehyde substrate.Using phenylacetaldehyde Using phenylacetaldehyde substrates, substrates, nearly equi nearlyvalent equivalent amounts amounts of the oftwo the twoproducts products could could be beachieved achieved by bya 30 a 30min min reaction reaction time, time, while while exte extendingnding the the time time to to 4 4 h producedproduced monosubstitutedmonosubstituted quinoline as the solesole product.product. However, aliphaticaliphatic aldehydesaldehydes gavegave onlyonly thethe disubstituteddisubstituted quinoline.quinoline. This phenomenonphenomenon was was rationalized rationalized through through mechanistic mechanistic inquiry. inquiry. The ionic The liquid ionic reaction liquid mediumreaction ismedium presumed is presumed to play anto play integral an integral part by part hydrogen by hydrogen bonding bonding with with the aldehyde, the aldehyde, thus thus increasing increasing its electrophilicity.its electrophilicity. The The aniline aniline1 attacks 1 attacks the aldehyde the aldehyde9, forming 9, forming an imine an imine through through loss of loss H2O. of This H2O. imine, This actingimine, throughacting through its enamine its enamine tautomer, tautomer, self-condenses self-condenses into a dimer. into Thisa dimer. dimer This then dimer cyclizes, then extruding cyclizes, theextruding starting the aniline, starting then aniline, oxidizes then tooxidizes the disubstituted to the disubstituted product 11aproduct. If the 11a R.2 Ifgroup the R2 is group aryl, aisbenzyl aryl, a radicalbenzyl radical could thencould form, then form, possibly possi withbly with assistance assistance from from the the ionic ioni liquidc liquid medium. medium. This This radical radical thenthen reacts with molecularmolecular oxygen to form thethe peroxyperoxy acid.acid. This peroxy acid isis extrudedextruded asas benzaldehydebenzaldehyde and hydroxide radical, leavingleaving thethe monosubstitutedmonosubstituted productproduct 11b11b..

3.3. Doebner–Von Miller Reaction The Doebner–Von MillerMiller (DVM)(DVM) reaction,reaction, an offshootoffshoot of the Skraup reaction in which an α,β-unsaturated carbonyl carbonyl compound replaces the glycerol component, is a commonly-usedcommonly-used route toward 2-substituted quinolines.quinolines. The original method was prone to acid-catalyzed polymerization of the carbonyl substrate, thereby resulting inin lowlow yieldsyields of product. Therefore the advent of a biphasic reaction mediummedium was was a a boon boon to to this this reaction; reaction; sequestering sequestering the carbonylthe carbonyl compound compound in an organicin an organic phase drasticallyphase drastically reduced reduced polymerization polymerization and increased and increa yieldsed[ 17yield]. However, [17]. However, the use the of use this of method this method in the formationin the formation of heteroring-unsubstituted of heteroring-unsubstitut quinolinesed quinolines remained remained unprecedented. unprecedented. Ramann and Cowen [18] [18] described the synthesis synthesis of of heteroring-uns heteroring-unsubstitutedubstituted quinolines through a modifiedmodified Doebner–Von MillerMiller route.route. After initial trialstrials using acrolein in a biphasic reaction medium, they foundfound acroleinacrolein diethyldiethyl acetal to bebe aa superiorsuperior annulationannulation partnerpartner (Figure(Figure9 9).). Interestingly,Interestingly, theythey found a biphasicbiphasic solvent mixture detrimental to the efficiencyefficiency of the reaction;reaction; performing the reaction solely in dilute HCl improved the outcome significantly,significantly, resulting in quinolines with a wide variety of substitution patterns in fair to excellent yields. The reaction is presumed to proceed through a typical Skraup–DVM mechanism [19], [19], with the aniline performingperforming conjugate addition to either protonated acrolein or an oxocarbeniumoxocarbenium ion, both of whichwhich areare possiblepossible acid-mediatedacid-mediated hydrolysis products of acrolein diethyl acetal. Dehydrative ring closure, followed by oxidative aromatization, results in the finalfinal quinoline products.

Figure 9. Doebner–Von Miller cyclization of anilines with acroleinacrolein diethyldiethyl acetal.acetal.

3.4. Conrad–Limpach Reaction 3.4. Conrad–Limpach Reaction Aryl amines and β-ketoesters are combined under thermal conditions to form quinoline-4-ols in Aryl amines and β-ketoesters are combined under thermal conditions to form quinoline-4-ols in the Conrad–Limpach reaction. Although this is considered a universal process [20], it presents several the Conrad–Limpach reaction. Although this is considered a universal process [20], it presents several challenges. The original solvent-free method was relatively inefficient, however the high-energy imine-enol intermediate compulsory for cyclization necessitated any solvent added to the mixture to

Molecules 2016, 21, 986 7 of 23

Moleculeschallenges. 2016, 21 The, 986 original solvent-free method was relatively inefﬁcient, however the high-energy7 of 22 imine-enol intermediate compulsory for cyclization necessitated any solvent added to the mixture to be high-boiling. The The mineral mineral oil, oil, diphenyl ether, ether, and Dowtherm A commonly used as solvents are either prohibitively expensive or difﬁcultdifficult toto removeremove fromfrom thethe productproduct [[21].21]. Khan and coworkers [[22]22] approached thethe synthesissynthesis ofof biologically-relevantbiologically-relevant 4-acetylquinolines4-acetylquinolines through a a Conrad–Limpach-like Conrad–Limpach-like mu multicomponentlticomponent reaction reaction (MCR). (MCR). As As an an atom-economical atom-economical way way to combineto combine three three or more or more molecules, molecules, MCRs MCRs are a powerful are a powerful tool in the tool construction in the construction of complex of structures complex [23];structures this tactic [23]; this was tactic utilized was utilizedin the information the formation of quinolines of quinolines via vianaphthylamine naphthylamine (14 (14, Figure, Figure 10),10), aldehyde ( (99),), and and ββ-ketoester-ketoester (15 (15) components) components under under camphorsulfonic camphorsulfonic acid acid (CSA, (CSA, 16) catalysis.16) catalysis. The Thereaction reaction is presumed is presumed to proceed to proceed through through a Michael-like a Michael-like γ-additionγ-addition of of the the CSA-activated CSA-activated β-ketoester-ketoester to the preformed imine. The resultant intermediate then cyclizes and aromatizes to give the product quinolines 17 inin excellentexcellent yield.yield. Notably, Notably, by by employin employingg this MCR approach, they avoided the high-energy intermediate common to this type of reac reactiontion and thus were able to perform the reaction in low-boiling acetonitrile.

Figure 10. Acid-catalyzed multicomponent Conrad–Limpach reaction. Figure 10. Acid-catalyzed multicomponent Conrad–Limpach reaction.

3.5. Povarov Reaction 3.5. Povarov Reaction As previously mentioned, multicomponent reactions make it possible to construct complex As previously mentioned, multicomponent reactions make it possible to construct complex compounds in a single atom-economical step. The Povarov reaction is an example of an established aza- compounds in a single atom-economical step. The Povarov reaction is an example of an heterocycle synthesis via MCR. Typically, the Povarov reaction proceeds via the inverse electron-demand established aza-heterocycle synthesis via MCR. Typically, the Povarov reaction proceeds via the Diels–Alder reaction of an aryl amine, aldehyde, and activated alkene to form tetrahydroquinolines. inverse electron-demand Diels–Alder reaction of an aryl amine, aldehyde, and activated alkene to Lin et al. [24] reported a molecular iodine-catalyzed version of the Povarov reaction (Figure 11), form tetrahydroquinolines. in which quinoline derivatives were obtained directly from aniline (1), aldehyde (9), and alkyne (18) Lin et al. [24] reported a molecular iodine-catalyzed version of the Povarov reaction (Figure 11), precursors. The aniline 1 first forms a Schiff base with the aldehyde 9, which then coordinates with in which quinoline derivatives were obtained directly from aniline (1), aldehyde (9), and alkyne (18) the Lewis acidic I2. This complex then regioselectively goes through a Diels–Alder cycloaddition with precursors. The aniline 1 ﬁrst forms a Schiff base with the aldehyde 9, which then coordinates with the the alkyne 18, forming a dihydro intermediate, which is oxidized by the ambient atmosphere to give Lewis acidic I . This complex then regioselectively goes through a Diels–Alder cycloaddition with the the 2- and 4-substituted2 quinoline 19 in fair to good yield. alkyne 18, forming a dihydro intermediate, which is oxidized by the ambient atmosphere to give the 2- and 4-substituted quinoline 19 in fair to good yield. NH R 10 mol% I N R2 2 O 3 2 + + MeNO R2 2 R 17 examples, 32-83% yield. R1 1 1918 19 R3

-H2O II [O]

R3 H N I2 N 18 N R2

R2 R2 Diels-Alder

R R R1 1 1 R3 Figure 11. Iodine-catalyzed multicomponent Povarov reaction.

Molecules 2016, 21, 986 7 of 22 be high-boiling. The mineral oil, diphenyl ether, and Dowtherm A commonly used as solvents are either prohibitively expensive or difficult to remove from the product [21]. Khan and coworkers [22] approached the synthesis of biologically-relevant 4-acetylquinolines through a Conrad–Limpach-like multicomponent reaction (MCR). As an atom-economical way to combine three or more molecules, MCRs are a powerful tool in the construction of complex structures [23]; this tactic was utilized in the formation of quinolines via naphthylamine (14, Figure 10), aldehyde (9), and β-ketoester (15) components under camphorsulfonic acid (CSA, 16) catalysis. The reaction is presumed to proceed through a Michael-like γ-addition of the CSA-activated β-ketoester to the preformed imine. The resultant intermediate then cyclizes and aromatizes to give the product quinolines 17 in excellent yield. Notably, by employing this MCR approach, they avoided the high-energy intermediate common to this type of reaction and thus were able to perform the reaction in low-boiling acetonitrile.

Figure 10. Acid-catalyzed multicomponent Conrad–Limpach reaction.

3.5. Povarov Reaction As previously mentioned, multicomponent reactions make it possible to construct complex compounds in a single atom-economical step. The Povarov reaction is an example of an established aza- heterocycle synthesis via MCR. Typically, the Povarov reaction proceeds via the inverse electron-demand Diels–Alder reaction of an aryl amine, aldehyde, and activated alkene to form tetrahydroquinolines. Lin et al. [24] reported a molecular iodine-catalyzed version of the Povarov reaction (Figure 11), in which quinoline derivatives were obtained directly from aniline (1), aldehyde (9), and alkyne (18) precursors. The aniline 1 first forms a Schiff base with the aldehyde 9, which then coordinates with the Lewis acidic I2. This complex then regioselectively goes through a Diels–Alder cycloaddition with

Moleculesthe alkyne2016 18, 21, ,forming 986 a dihydro intermediate, which is oxidized by the ambient atmosphere to8 give of 23 the 2- and 4-substituted quinoline 19 in fair to good yield.

NH R 10 mol% I N R2 2 O 3 2 + + MeNO R2 2 R 17 examples, 32-83% yield. R1 1 1918 19 R3

-H2O II [O]

R3 H N I2 N 18 N R2

R2 R2 Diels-Alder

R R R1 1 1 R3

Figure 11. Iodine-catalyzed multicom multicomponentponent Povarov reaction. Molecules 2016, 21, 986 8 of 22

Wu and coworkers [[25]25] recently described another I2-catalyzed-catalyzed Povarov-type reaction, in which they envisioned envisioned a amore more complex complex role role for foriodine iodine in the in presence the presence of arylamines, of arylamines, methylketones, methylketones, and α- ketoestersand α-ketoesters (Figure (Figure12). They 12 prop). Theyose addition propose of addition iodine from of iodineI2 to the from alpha-carbon I2 to the of alpha-carbon methyl ketone of 20methyl. The solvent ketone DMSO20. The then solvent oxidizes DMSO the α-iodo then oxidizesketone, which the α is-iodo subsequently ketone, which attacked is by subsequently the aniline 1attacked. The resultant by the C-acyliminium aniline 1. The resultant reacts with C-acyliminium the ketoester reactsenol tautomer with the 21a ketoester. Electrophilic enol tautomer cyclization,21a. followedElectrophilic by oxidative cyclization, aromatization, followed by oxidativegives the 2,4-disubstituted aromatization, gives product the 2,4-disubstituted 22. product 22.

Figure 12. Iodine-catalyzed Povarov reaction. Figure 12. Iodine-catalyzed Povarov reaction.

4. Quinoline Synthesis via Modifications to Non-Aniline-Based Established Methods 4. Quinoline Synthesis via Modiﬁcations to Non-Aniline-Based Established Methods

4.1. Pfitzinger Pfitzinger Reaction The Pfitzinger Pfitzinger reaction reaction is a isdivergent a divergent approach approach to the synthesis to the of synthesis 2-substituted of 2-substituted quinoline-4- quinoline-4-carboxyliccarboxylic acids by the reaction acids by of isatin the reaction with ketone of isatins in the with presence ketones of ain stro theng presencenucleophile of (typically a strong hydroxide).nucleophile Pfitzinger’s (typically hydroxide). own studies Pfitzinger’s of the late nineteenth own studies century of the indicate late nineteenth this reaction century is generally indicate efficient-hethis reaction reported is generally obtaining efficient-he 2-methylquinoline-4-ca reported obtainingrboxylic 2-methylquinoline-4-carboxylic acid in up to 80% yield [26]. acidHowever, in up thereto 80% are yield also [ 26less-efficient]. However, examples there are of also this less-efficient reaction, owing examples to a thick of this resin reaction, surrounding owing the to a crude thick productresin surrounding and hampering the crude isolation product [27]. andRecent hampering research isolationon this reaction [27]. Recent documents research novel on substitutions this reaction ondocuments the quinoline novel system. substitutions on the quinoline system. Zhu andand coworkerscoworkers [ 28[28],], noting noting the the dearth dearth of methodsof methods to obtain to obtain quinoline-4-carboxylic quinoline-4-carboxylic acids acidsunsubstituted unsubstituted in the in 2-position,the 2-position, utilized utilized the the Pfitzinger Pfitzinger reaction reaction in in combination combination withwith selective decarboxylation to to obtain obtain these these analogs analogs (Figure (Figure 13). 13 Reacting). Reacting isatin isatin 23 with23 with sodium sodium pyruvate pyruvate 24 in an24 aqueousin an aqueous solution solution of sodium of sodium hydroxide hydroxide under under microwave microwave irradiation, irradiation, they they were were able able to to obtain obtain the desired quinoline-2,4-dicarboxylic acidsacids 25.. These were then subjected subjected to to short short microwave microwave irradiation irradiation at 190–200 ˝°CC toto selectivelyselectively decarboxylatedecarboxylate at at the the 2-position, 2-position, leaving leaving the the quinoline-4-carboxylic quinoline-4-carboxylic acids acids26 26in overallin overall very very good good yield. yield.

Figure 13. Pfitzinger reaction under microwave irradiation with selective decarboxylation.

Perumal et al. [29] achieved aminouracil-substituted isoxazolsquinolines through a Pfitzinger multicomponent reaction (Figure 14). Under a catalytic amount of p-toluenesulfonic acid, isatin 23 and 6-aminouracil 27 undergo aldol addition and ring opening to give isatic acid. The enol tautomer of isoxazole 28a attacks the isatinic acid, and attack of the amine on isoxazole carbonyl forms a seven-member ring. With loss of H2O, the ring contracts, and decarboxylation aromatizes the ring, giving the final quinoline product 29 in excellent yield.

Molecules 2016, 21, 986 8 of 22

Wu and coworkers [25] recently described another I2-catalyzed Povarov-type reaction, in which they envisioned a more complex role for iodine in the presence of arylamines, methylketones, and α- ketoesters (Figure 12). They propose addition of iodine from I2 to the alpha-carbon of methyl ketone 20. The solvent DMSO then oxidizes the α-iodo ketone, which is subsequently attacked by the aniline 1. The resultant C-acyliminium reacts with the ketoester enol tautomer 21a. Electrophilic cyclization, followed by oxidative aromatization, gives the 2,4-disubstituted product 22.

Figure 12. Iodine-catalyzed Povarov reaction.

4. Quinoline Synthesis via Modifications to Non-Aniline-Based Established Methods

4.1. Pfitzinger Reaction The Pfitzinger reaction is a divergent approach to the synthesis of 2-substituted quinoline-4- carboxylic acids by the reaction of isatin with ketones in the presence of a strong nucleophile (typically hydroxide). Pfitzinger’s own studies of the late nineteenth century indicate this reaction is generally efficient-he reported obtaining 2-methylquinoline-4-carboxylic acid in up to 80% yield [26]. However, there are also less-efficient examples of this reaction, owing to a thick resin surrounding the crude product and hampering isolation [27]. Recent research on this reaction documents novel substitutions on the quinoline system. Zhu and coworkers [28], noting the dearth of methods to obtain quinoline-4-carboxylic acids unsubstituted in the 2-position, utilized the Pfitzinger reaction in combination with selective decarboxylation to obtain these analogs (Figure 13). Reacting isatin 23 with sodium pyruvate 24 in an aqueous solution of sodium hydroxide under microwave irradiation, they were able to obtain the desired quinoline-2,4-dicarboxylic acids 25. These were then subjected to short microwave irradiation atMolecules 190–2002016 °C, 21 to, 986 selectively decarboxylate at the 2-position, leaving the quinoline-4-carboxylic acids9 of 23 26 in overall very good yield.

FigureFigure 13. 13. PfitzingerPﬁtzinger reaction reaction under under microwave microwave irra irradiationdiation with selective decarboxylation.

Perumal et al. [29] achieved aminouracil-substituted isoxazolsquinolines through a Pfitzinger Perumal et al. [29] achieved aminouracil-substituted isoxazolsquinolines through a Pfitzinger multicomponent reaction (Figure 14). Under a catalytic amount of p-toluenesulfonic acid, isatin 23 multicomponent reaction (Figure 14). Under a catalytic amount of p-toluenesulfonic acid, isatin 23 and and 6-aminouracil 27 undergo aldol addition and ring opening to give isatic acid. The enol tautomer 6-aminouracil 27 undergo aldol addition and ring opening to give isatic acid. The enol tautomer of isoxazole 28a attacks the isatinic acid, and attack of the amine on isoxazole carbonyl forms a of isoxazole 28a attacks the isatinic acid, and attack of the amine on isoxazole carbonyl forms seven-member ring. With loss of H2O, the ring contracts, and decarboxylation aromatizes the ring, a seven-member ring. With loss of H O, the ring contracts, and decarboxylation aromatizes the giving the final quinoline product 29 in 2excellent yield. ring,Molecules giving 2016, the21, 986 final quinoline product 29 in excellent yield. 9 of 22 Molecules 2016, 21, 986 9 of 22 O O N O N O N N NH2 O O 20 mol % p-TSA-H O N O 2 O NH O + + 2 20 mol % p-TSA-H2O O N N O ON H O O + O N NH + 2 N H 2 R1 23 N 27 ON28 H89%O O O N NH2 2 N N R1 23 H 27 28 89% 29 O aldol ring N aromatization addition opening 29 aldol ring -CO2 aromatizationO addition opening O -CO 2 O N O N N O N N N NH2 O N HO O N O COOH HO N + N NH2 O O NH HO ON ring O HO 2 + N NH COOH addition, N 2 contraction N O NH2 ON28a O OH ring OH ring opening HO NHOH2 N ON 28a addition, OH contraction NH O -H O O R1 2 OH ringring opening closure HO OH 2 N NH -H O R1 2 ring closure NN 2 O NN O Figure 14. Acid-catalyzed multicomponent PfitzingerPfitzinger reaction.reaction. Figure 14. Acid-catalyzed multicomponent Pfitzinger reaction. Elghamry and Al-Faiyz [30] investigated the use of enaminones as the annulation partner in the Elghamry and Al-Faiyz [30] investigated the use of enaminones as the annulation partner in the PfitzingerElghamry synthesis and Al-Faiyz of 3-aroylketone [30] investigated quinoline-4-ca the userboxylic of enaminones acids (Figure as the 15). annulation In aqueous partner sodium in the or Pfitzinger synthesis of 3-aroylketone quinoline-4-carboxylic acids (Figure 15). In aqueous sodium Pfitzingerpotassium synthesis hydroxide, of 3-aroylketonethe isatin (23) quinoline-4-ca ring opens, givingrboxylic isatinate. acids (Figure Aldol-like 15). Inaddition aqueous of sodium the alpha or or potassium hydroxide, the isatin (23) ring opens, giving isatinate. Aldol-like addition of the alpha potassiumcarbon of the hydroxide, enaminone the 30 isatin to isatinate (23) ring gives opens, an intermediate, giving isatinate. which Aldol-like cyclizes under addition acidic of conditions. the alpha carbon of the enaminone 30 to isatinate gives an intermediate, which cyclizes under acidic conditions. carbonLoss of of H the2O gives enaminone the aromatized 30 to isatinate product gives 31 an in intermediate, excellent yield. which cyclizes under acidic conditions. Loss of H O gives the aromatized product 31 in excellent yield. Loss of H2O gives the aromatized product 31 in excellent yield.

Figure 15. Pfitzinger reaction using enaminones under basic conditions. Figure 15. PfitzingerPﬁtzinger reaction using enaminones under basic conditions. 4.2. Friedländer Reaction 4.2. Friedländer Reaction Among the many established methods of quinoline synthesis, the Friedländer reaction is one of the oldest,Among and the one many of theestablished simplest. methods Its popularity of quinoline stems mainlysynthesis, from the its Friedlände versatility;r reaction many functional is one of thegroups oldest, are andwell one tolerated of the onsimplest. both the Its arylamine popularity and stems ketone mainly compon froments. its However,versatility; this many reaction functional is not groupswithout are its welldrawbacks. tolerated For on instance, both the regioselectivityarylamine and isketone difficult compon to controlents. However,when unsymmetrical this reaction ketone is not withoutannulation its drawbacks.partners are For used, instance, resulting regioselectivity in the formation is difficult of both to control 2-substituted when unsymmetrical and 2,3-disubstituted ketone annulationproducts [31].partners Therefore, are used, several resulting groups in the have formation recently of reportedboth 2-substituted modified and procedures 2,3-disubstituted of this productsvenerable [31].method. Therefore, several groups have recently reported modified procedures of this venerableSeveral method. versions of Brønsted acid-mediated Friedländer quinoline synthesis have appeared in the literatureSeveral versions in the last of fewBrønsted years. acid-mediated One example wasFriedländer reported quinoline by Dughera synthesis and coworkers have appeared [32], who in thehad literature previously in utilizedthe last fewthe acidyears. catalyst One example o-benzenedisulfonimide was reported by (Dughera34, Figure and 16) coworkers in several syntheses[32], who hadand previouslyfound it to utilized be non-corrosive, the acid catalyst non-volatile, o-benzenedisulfonimide and recyclable. They (34, Figureapplied 16) this in severalacid catalyst syntheses to a andsolvent-free found it Friedländer to be non-corrosive, reaction of non-volatile, 2-aminoarylketones and recyclable. (32) with They various applied carbonyl this acid compounds catalyst (to33 a). solvent-freeIn this way, Friedländer they obtained reacti seveonral of 2-aminoarylketones2,3-disubstituted quinolines (32) with (various35), including carbonyl fused compounds five-member (33). Inrings, this with way, good they to obtained excellent seve yields.ral 2,3-disubstituted quinolines (35), including fused five-member rings, with good to excellent yields.

Molecules 2016, 21, 986 10 of 23

4.2. Friedländer Reaction Among the many established methods of quinoline synthesis, the Friedländer reaction is one of the oldest, and one of the simplest. Its popularity stems mainly from its versatility; many functional groups are well tolerated on both the arylamine and ketone components. However, this reaction is not without its drawbacks. For instance, regioselectivity is difficult to control when unsymmetrical ketone annulation partners are used, resulting in the formation of both 2-substituted and 2,3-disubstituted products [31]. Therefore, several groups have recently reported modified procedures of this venerable method. Several versions of Brønsted acid-mediated Friedländer quinoline synthesis have appeared in the literature in the last few years. One example was reported by Dughera and coworkers [32], who had previously utilized the acid catalyst o-benzenedisulfonimide (34, Figure 16) in several syntheses and found it to be non-corrosive, non-volatile, and recyclable. They applied this acid catalyst to a solvent-free Friedländer reaction of 2-aminoarylketones (32) with various carbonyl compounds (33). In this way, they obtained several 2,3-disubstituted quinolines (35), including fused five-member rings, Moleculeswith good 2016 to, 21 excellent, 986 yields. 10 of 22 Molecules 2016, 21, 986 10 of 22 Molecules 2016, 21, 986 10 of 22

Figure 16. Brønsted acid-mediated Friedländer quinoline synthesis. FigureFigure 16. BrønstedBrønsted acid-mediated acid-mediated Friedländer Friedländer quinoline synthesis. Figure 16. Brønsted acid-mediated Friedländer quinoline synthesis. Zhu et al. [33] used p-toluenesulfonic acid as a catalyst in their pursuit of elusive 4-alkylquinolines Zhu et al. [33] [33] used used p-toluenesulfonic-toluenesulfonic acid acid as as a a catalyst catalyst in in their their pursuit pursuit of of elusive elusive 4-alkylquinolines 4-alkylquinolines (37, FigureZhu et al.17). [33] Refluxing used p-toluenesulfonic the carbonyl component acid as a catalyst 33 with in 2-alkynylanilinestheir pursuit of elusive 36 in 4-alkylquinolines ethanol initially (37, Figure 1717).). Refluxing Reﬂuxing the the carbonyl carbonyl component component 3333 with 2-alkynylanilines 3636 inin ethanol ethanol initially initially (resulted37, Figure in 17).acid-mediated Refluxing thehydration carbonyl of component the alkyne 33 to withthe corresponding2-alkynylanilines ketones 36 in 36aethanol. These initially then resultedresulted in acid-mediated hydration of the alkyne to thethe correspondingcorresponding ketonesketones 36a36a.. These These then resultedcyclized inin aacid-mediated typical Friedländer hydration fashion, of givingthe alkyne the desired to the 4-alkylquinolinescorresponding ketones 37 in moderate 36a. These to thenvery cyclized in a typical typical Friedländer Friedländer fashion, fashion, giving giving the the desired desired 4-alkylquinolines 4-alkylquinolines 37 inin moderate moderate to to very very cyclizedgood yield. in a typical Friedländer fashion, giving the desired 4-alkylquinolines 37 in moderate to very good yield. good yield.

Figure 17. Brønsted acid-mediated Friedländer reaction starting from 2-alkynylanilines. Figure 17. Brønsted acid-mediated Friedländer reaction starting from 2-alkynylanilines. FigureFigure 17. 17. BrønstedBrønsted acid-mediated acid-mediated Friedländer Friedländer reaction reaction starting starting from from 2-alkynylanilines. 2-alkynylanilines. Reddy et al. [34] also investigated Brønsted acid catalysts in Friedländer reactions. They found Reddy et al. [34] also investigated Brønsted acid catalysts in Friedländer reactions. They found the solidReddyReddy acid et et al. al.Chitosan-SO [34] [34] also investigated 3H (Figure Brønsted18) to be acid a highly catalysts efficient in Friedländer catalyst reactions.in the annulation They They found found of the solid acid Chitosan-SO3H (Figure 18) to be a highly efficient catalyst in the annulation of the2-aminoarylketonesthe solid solid acid acid Chitosan-SO Chitosan-SO 32 with various33HH (Figure (Figure carbonyl 18)18) to tocompounds be be a a highly highly 33 , efficientincluding efficient catalyst catalyst cyclic and in in stericallythe the annulation annulation hindered of of 2-aminoarylketones 32 with various carbonyl compounds 33, including cyclic and sterically hindered 2-aminoarylketonesexamples2-aminoarylketones to give diverse 32 withwith 2,3,4-trisubstituted various various carbonyl carbonyl quinolines compounds compounds 38 33 33in, , veryincluding including good cyclicyield cyclic afterand and sterically stericallyshort reflux hindered hindered times. examples to give diverse 2,3,4-trisubstituted quinolines 38 in very good yield after short reflux times. examplesInexamples addition, to to give givethey diverse diversewere gratified 2,3,4-trisubstituted 2,3,4-trisubstituted to find that quinolines quinolinesthe solid acid3838 inin wasvery very easily good good yieldrecovered yield after after shortfrom short refluxthe reflux reaction times. times. In addition, they were gratified to find that the solid acid was easily recovered from the reaction Inmixture,In addition, addition, reactivated, they they were were and gratified gratified reused withto to find find comparable that that the the solid solidsuccess. acid acid was was easily easily recovered recovered from from the the reaction reaction mixture, reactivated, and reused with comparable success. mixture,mixture, reactivated, reactivated, and reused with comparable success.

Figure 18. Chitosan-SO3H-catalyzed Friedländer quinoline synthesis. Figure 18. Chitosan-SO3H-catalyzed Friedländer quinoline synthesis. FigureFigure 18. Chitosan-SOChitosan-SO3H-catalyzedH-catalyzed Friedländer Friedländer quinoline quinoline synthesis. synthesis. Additionally, Lewis acid catalysis has3 featured in recent literature on the Friedländer quinoline Additionally, Lewis acid catalysis has featured in recent literature on the Friedländer quinoline synthesis.Additionally, Gu and Lewis coworkers acid catalysis [35] reported has featured the Lewis in recent acid-catalyzed literature on formationthe Friedländer of unexpected quinoline synthesis. Gu and coworkers [35] reported the Lewis acid-catalyzed formation of unexpected synthesis.benzazepine-fused Gu and quinoline coworkers products [35] reported from 2-amin theobenzaldehydes, Lewis acid-catalyzed 2-methylindole, formation and of acetophenone unexpected benzazepine-fused quinoline products from 2-aminobenzaldehydes, 2-methylindole, and acetophenone benzazepine-fused(Figure 19). The quinolineproposed products mechanism from 2-amin beginsobenzaldehydes, with Lewis 2-methylindole,acid-mediated andcombination acetophenone of (Figure 19). The proposed mechanism begins with Lewis acid-mediated combination of (Figure2-aminobenzaldehyde 19). The proposed 39 with 2-methylindolemechanism begins 40. This with intermediate Lewis acid-mediated then goes through combination nucleophilic of 2-aminobenzaldehyde 39 with 2-methylindole 40. This intermediate then goes through nucleophilic 2-aminobenzaldehydecyclization, followed by39 withC-N 2-methylindolebond cleavage. 40Th. Thise free intermediate arylamine then goesattacks through acetophenone nucleophilic 41, cyclization, followed by C-N bond cleavage. The free arylamine then attacks acetophenone 41, cyclization,forming an adduct,followed which by C-Nthen undergoesbond cleavage. an enamin The freee-activated arylamine Mannich-like then attacks cyclization acetophenone to form the41, forming an adduct, which then undergoes an enamine-activated Mannich-like cyclization to form the formingbenzazepine-fused an adduct, quinolineswhich then 42 undergoes in fair to anexcellent enamin yields.e-activated Mannich-like cyclization to form the benzazepine-fused quinolines 42 in fair to excellent yields. benzazepine-fused quinolines 42 in fair to excellent yields.

Molecules 2016, 21, 986 11 of 23

Additionally, Lewis acid catalysis has featured in recent literature on the Friedländer quinoline synthesis. Gu and coworkers [35] reported the Lewis acid-catalyzed formation of unexpected benzazepine-fused quinoline products from 2-aminobenzaldehydes, 2-methylindole, and acetophenone (Figure 19). The proposed mechanism begins with Lewis acid-mediated combination of 2-aminobenzaldehyde 39 with 2-methylindole 40. This intermediate then goes through nucleophilic cyclization, followed by C-N bond cleavage. The free arylamine then attacks acetophenone 41, forming an adduct, which then undergoes an enamine-activated Mannich-like cyclization to form the benzazepine-fused quinolines 42 in fair to excellent yields. Molecules 2016, 21, 986 11 of 22

Molecules 2016, 21, 986 11 of 22

Figure 19. Lewis acid-catalyzed Friedländer quinoline synthesis. Figure 19. Lewis acid-catalyzed Friedländer quinoline synthesis. Guo et al. found similarly unforeseen success with a related Lewis acid-catalyzed multicomponent reactionGuo et of al. 2-aminobenzaldehydes foundFigure similarly 19. Lewis acid-catalyzed unforeseenand 2-methylindole. Friedländer success quinoline withHowever, a synthesis. related the third Lewis component, acid-catalyzed multicomponentbis(methylsulfanyl) reaction phenylpropenon of 2-aminobenzaldehydese, showed divergent and reactivity 2-methylindole. as compared However,to acetophenone the third component,(FigureGuo 20). bis(methylsulfanyl)et al.The found reaction similarly is presumed unforeseen phenylpropenone, to proceedsuccess with through a showed related a similar Lewis divergent mechanism, acid-catalyzed reactivity beginning multicomponent as comparedwith the to acetophenoneBFreaction3-mediated of (Figure coupling2-aminobenzaldehydes 20 ).of 2-aminoacetophenone The reaction and is presumed2-methylindole. 39 and 2-methylindole to proceed However, through 40 the. Then, third a similarafter component, cyclization mechanism, andbis(methylsulfanyl) C-N bond cleavage, phenylpropenon the arylaminee, showedattacks bis(methylsulfanyl)divergent reactivity phenylpropenone as compared to acetophenone43, extruding beginning with the BF3-mediated coupling of 2-aminoacetophenone 39 and 2-methylindole 40. methylsulfide(Figure 20). The and reaction forming is thepresumed final quinoline to proceed product through 44 in a goodsimilar to mechanism,excellent yield. beginning with the Then, after cyclization and C-N bond cleavage, the arylamine attacks bis(methylsulfanyl) BF3-mediated coupling of 2-aminoacetophenone 39 and 2-methylindole 40. Then, after cyclization phenylpropenoneand C-N bond 43cleavage,, extruding the arylamine methylsulﬁde attacks and bis(methylsulfanyl) forming the ﬁnal phenylpropenone quinoline product 43, extruding44 in good to excellentmethylsulfide yield. and forming the final quinoline product 44 in good to excellent yield.

Figure 20. Lewis acid-catalyzed multicomponent Friedländer quinoline synthesis with dithioethers.

Lewis bases can also play a catalytic role in the synthesis of quinolines. Kwon et al. [36] reported a robustFigure phosphine-catalyzed 20. Lewis acid-catalyzed annulation multicomponent of N-tosylated Friedländer 2-aminoaryl quinoline synthesis aldehydes with and dithioethers. ketones with Figure 20. Lewis acid-catalyzed multicomponent Friedländer quinoline synthesis with dithioethers. alkynes to give dihydroquinolines, which were easily converted to the quinoline by a quench with diluteLewis HCl (Figurebases can 21). also Kwon play proposeda catalytic three role in pote thential synthesis mechanisms of quinolines. for the Kwon reaction et al. and [36] attempted reported toa robustpositively phosphine-catalyzed identify the correct annulation pathway by of piNnpointing-tosylated key2-aminoaryl intermediates aldehydes via NMR and studies. ketones While with thisalkynes was ultimatelyto give dihydroquinolines, unfruitful, they determined which were the easilyreaction converted to most likely to the proc quinolineeed through by a a quench general withbase catalysisdilute HCl mechanism. (Figure 21). The Kwon alkyne proposed 18 is first activatedthree pote byntial the phosphinmechanismse and for subsequently the reaction deprotonates and attempted the amineto positively 45, which identify is rendered the correct more pathway acidic due by topi thenpointing tosyl group. key intermediates The amine nucleophile via NMR studies.45a then While adds tothis a wassecond ultimately alkyne unfruitful,molecule, theywhich determined cyclizes, deprotonatesthe reaction to another most likely tosylated proceed amine, through then a general aromatizes base undercatalysis acidic mechanism. quench Theto the alkyne product 18 is quinoline first activated 46. by the phosphine and subsequently deprotonates the amine 45, which is rendered more acidic due to the tosyl group. The amine nucleophile 45a then adds to a second alkyne molecule, which cyclizes, deprotonates another tosylated amine, then aromatizes under acidic quench to the product quinoline 46.

Molecules 2016, 21, 986 12 of 23

Lewis bases can also play a catalytic role in the synthesis of quinolines. Kwon et al. [36] reported a robust phosphine-catalyzed annulation of N-tosylated 2-aminoaryl aldehydes and ketones with alkynes to give dihydroquinolines, which were easily converted to the quinoline by a quench with dilute HCl (Figure 21). Kwon proposed three potential mechanisms for the reaction and attempted to positively identify the correct pathway by pinpointing key intermediates via NMR studies. While this was ultimately unfruitful, they determined the reaction to most likely proceed through a general base catalysis mechanism. The alkyne 18 is ﬁrst activated by the phosphine and subsequently deprotonates the amine 45, which is rendered more acidic due to the tosyl group. The amine nucleophile 45a then adds to a second alkyne molecule, which cyclizes, deprotonates another tosylated amine, then aromatizesMolecules under 2016, 21 acidic, 986 quench to the product quinoline 46. 12 of 22

Molecules 2016, 21, 986 12 of 22 1. 10 mol% PPh O 3 R2 MeCN, rt R 2. 1M HCl, 5 min 3 R2 1. 10 mol% PPh R3 + O 3 R2 18 21 examples,MeCN, 30-99% rt yield. R NHTs 2. 1M HCl, 5 min N 3 R R2 3 + R1 45 R1 46 PPh 3 21 examples, 30-99% yield. 18 NHTs HCl quenchN-TsCl, H2O R 45 R1 46 1 HO R2 + PPh3 Ph P HCl quench -TsCl,R H2O 3 - 3 C HO R + 2 Ph P R R 3 - 3 O O aldol N 3 Michael C addition R1 Ts R R2 addition R2 deprotonation3 O O aldol N - Michael - addition R145a Ts N R addition N R C R 2 R 2 deprotonation 1 Ts 1 Ts R 45 45a - R3 -3 45a N N C R 18 R 1 Ts 1 Ts R 45 45a R3 3 18 FigureFigure 21. 21.Phosphine-catalyzed Phosphine-catalyzed FriedländerFriedländer quinoline quinoline synthesis. synthesis.

Zhu and Cai [37]Figure used 21. N-heterocyclic Phosphine-catalyzed carbenes Friedländer (NHCs), quinoline another synthesis. type of Lewis base, to obtain Zhudiversely and substituted Cai [37] used quinolines N-heterocyclic from 2-aminobenzy carbenesl alcohols (NHCs), and another ketones type (Figure of 22). Lewis They base, proposed to obtain Zhu and Cai [37] used N-heterocyclic carbenes (NHCs), another type of Lewis base, to obtain diverselythe NHC-generated substituted quinolines in situ from from deprotonation 2-aminobenzyl of the alcohols precursor and 48 ketones by hydroxide-may (Figure 22). assist They in proposed the diversely substituted quinolines from 2-aminobenzyl alcohols and ketones (Figure 22). They proposed the NHC-generatedtandem proton and in situhydride from transfer deprotonation from the benzyl of the alcohol precursor 47 to48 theby ketone hydroxide-may 33. This creates assist the in the the NHC-generated in situ from deprotonation of the precursor 48 by hydroxide-may assist in the tandemactive proton intermediates, and hydride which transfer undergo from crossed the benzyl aldol addition alcohol and47 to then the cyclize ketone with33. Thisloss of creates H2O to the give active tandem proton and hydride transfer from the benzyl alcohol 47 to the ketone 33. This creates the intermediates,the final quinoline which undergoproducts 49 crossed in good aldol to excellent addition yield. and then cyclize with loss of H O to give the active intermediates, which undergo crossed aldol addition and then cyclize with loss of H22O to give ﬁnal quinolinethe final quinoline products products49 in good 49 in good to excellent to excellent yield. yield.

Figure 22. N-Heterocyclic carbene-catalyzed Friedländer quinoline synthesis. Figure 22. N-Heterocyclic carbene-catalyzed Friedländer quinoline synthesis. CitingFigure the inherent 22. N-Heterocyclic electrophilic and carbene-catalyzed nucleophilic character Friedländer of allenoates quinoline ( synthesis.α-allenic esters), Selig and Raven [38] investigated the use of these compounds in the formation of quinolines. Although their Citing the inherent electrophilic and nucleophilic character of allenoates (α-allenic esters), Selig initial trials using o-aminobenzaldehyde did not result in the cyclization product, they found that and Raven [38] investigated the use of these compounds in the formation of quinolines. Although their monoprotection of the amine allowed the process to occur. Interestingly, they observed formation of initial trials using o-aminobenzaldehyde did not result in the cyclization product, they found that both the desired quinoline product as well as a second product that featured a migration of the monoprotection of the amine allowed the process to occur. Interestingly, they observed formation of protecting group and formation of a new quaternary center (Figure 23). They propose the mechanism both the desired quinoline product as well as a second product that featured a migration of the to operate through an aza-Michael addition of the Brønsted base-promoted amide anion of the protecting group and formation of a new quaternary center (Figure 23). They propose the mechanism 2-aminobenzaldehyde 50 to the β carbon of the allenoate 51, which then cyclizes selectively from the to operate through an aza-Michael addition of the Brønsted base-promoted amide anion of the γ position. The resultant intermediate can then be depicted in its zwitterionic form, from which it 2-aminobenzaldehyde 50 to the β carbon of the allenoate 51, which then cyclizes selectively from the performs a 1,3-shift of the protecting group to give the product. Under optimized reaction conditions, γ position. The resultant intermediate can then be depicted in its zwitterionic form, from which it they were able to selectively synthesize the rearrangement products 52 in high yields using various performs a 1,3-shift of the protecting group to give the product. Under optimized reaction conditions, protecting groups. they were able to selectively synthesize the rearrangement products 52 in high yields using various

protecting groups.

Molecules 2016, 21, 986 13 of 23

Citing the inherent electrophilic and nucleophilic character of allenoates (α-allenic esters), Selig and Raven [38] investigated the use of these compounds in the formation of quinolines. Although their initial trials using o-aminobenzaldehyde did not result in the cyclization product, they found that monoprotection of the amine allowed the process to occur. Interestingly, they observed formation of both the desired quinoline product as well as a second product that featured a migration of the protecting group and formation of a new quaternary center (Figure 23). They propose the mechanism to operate through an aza-Michael addition of the Brønsted base-promoted amide anion of the 2-aminobenzaldehyde 50 to the β carbon of the allenoate 51, which then cyclizes selectively from the γ position. The resultant intermediate can then be depicted in its zwitterionic form, from which it performs a 1,3-shift of the protecting group to give the product. Under optimized reaction conditions, they were able to selectively synthesize the rearrangement products 52 in high yields using various protectingMolecules 2016 groups., 21, 986 13 of 22 Molecules 2016, 21, 986 13 of 22

Figure 23. Base-mediated cyclization of 2-am 2-aminobenzaldehydesinobenzaldehydes with allenoates. Figure 23. Base-mediated cyclization of 2-aminobenzaldehydes with allenoates. As with the previously mentioned Skraup and Doebner reactions, the Friedländer quinoline As with the previously mentioned Skraup and Doebner reactions, the Friedländer quinoline synthesisAs with can bethe improved previously by mentionedthe use of ionic Skraup liquids and as Doebner either solven reactions,t or catalyst. the Friedländer Tajik and coworkersquinoline synthesis can be improved by the use of ionic liquids as either solvent or catalyst. Tajik and synthesis[39] reported can bean improved efficient quinolby the ineuse synthesisof ionic liquids using as substoichiometric either solvent or catalyst.amounts Tajik of the and ionic coworkers liquid [39]coworkers reported [39 ]an reported efficient an quinol efﬁcientine quinolinesynthesis synthesisusing substoichiometric using substoichiometric amounts amounts of the ionic of the liquid ionic [bmim]HSO4 (3c, Figure 24). The short reaction time, high yield, and solvent-free conditions liquid [bmim]HSO4 (3c, Figure 24). The short reaction time, high yield, and solvent-free conditions [bmim]HSOrecommend this (3c procedure, Figure4 24). as aThe green short alternative reaction to traditionaltime, high Friedländeryield, and reactions.solvent-free conditions recommend this procedure as aa greengreen alternativealternative toto traditionaltraditional FriedländerFriedländer reactions.reactions.

Figure 24. Ionic liquid-catalyzed Friedländer quinoline synthesis. Figure 24. IonicIonic liquid-catalyzed liquid-catalyzed Friedländer Friedländer quinoline synthesis. Sarma et al. [40] also investigated the use of Brønsted-acidic ionic liquids as catalysts in a classical Sarma et al. [40] also investigated the use of Brønsted-acidic ionic liquids as catalysts in a classical FriedländerSarma etreaction al. [40] (Figure also investigated 25). They thefound use their of Brønsted-acidic novel ionic liquid ionic catalyst liquids [Msim][OOCCCl as catalysts in a classical3] 3d to Friedländer reaction (Figure 25). They found their novel ionic liquid catalyst [Msim][OOCCCl3] 3d to beFriedländer at least as reaction efficient (Figure as other 25 known). They ionic found liquids their noveland acid ionic catalysts, liquid catalyst producing [Msim][OOCCCl quinolines in ]yields3d to be at least as efficient as other known ionic liquids and acid catalysts, producing quinolines in3 yields upbe atto least100%. as In efﬁcient addition, as otherthe ability known to ionicrecycle liquids and reuse and acidthis catalysts,catalyst was producing particularly quinolines appealing. in yields up to 100%. In addition, the ability to recycle and reuse this catalyst was particularly appealing. up to 100%. In addition, the ability to recycle and reuse this catalyst was particularly appealing.

Figure 25. Ionic liquid acid-catalyzed Friedländer quinoline synthesis. Figure 25. Ionic liquid acid-catalyzed Friedländer quinoline synthesis. Citing its recent application to the preparation of heterocycles, Augustine and coworkers exploredCiting the its use recent of peptide application coupling to agtheent preparat propylphosphonicion of heterocycles, anhydride Augustine (T3P, 55, Figureand coworkers 26) in the exploredFriedländer the reaction. use of peptide They were coupling gratified agent to propylphosphonic find that a catalytic anhydride loading of(T3P, T3P 55 to, Figurethe reaction 26) in was the Friedländersufficient to reaction.give very They high wereyields gratified of diversely-substituted to find that a catalytic quinolines. loading Mechanistically, of T3P to the theyreaction propose was sufficientT3P to assist to give in the very initial high condensation yields of diversely-substituted of 32 and 33, as well quinolines. as the subsequent Mechanistically, intramolecular they propose aldol T3Pcondensation to assist in to the form initial the finalcondensation product 56 of. 32 and 33, as well as the subsequent intramolecular aldol condensation to form the final product 56.

Molecules 2016, 21, 986 13 of 22

Figure 23. Base-mediated cyclization of 2-aminobenzaldehydes with allenoates.

As with the previously mentioned Skraup and Doebner reactions, the Friedländer quinoline synthesis can be improved by the use of ionic liquids as either solvent or catalyst. Tajik and coworkers [39] reported an efficient quinoline synthesis using substoichiometric amounts of the ionic liquid [bmim]HSO4 (3c, Figure 24). The short reaction time, high yield, and solvent-free conditions recommend this procedure as a green alternative to traditional Friedländer reactions.

Figure 24. Ionic liquid-catalyzed Friedländer quinoline synthesis.

Sarma et al. [40] also investigated the use of Brønsted-acidic ionic liquids as catalysts in a classical Friedländer reaction (Figure 25). They found their novel ionic liquid catalyst [Msim][OOCCCl3] 3d to Moleculesbe 2016at least, 21, as 986 efficient as other known ionic liquids and acid catalysts, producing quinolines in yields14 of 23 up to 100%. In addition, the ability to recycle and reuse this catalyst was particularly appealing.

Figure 25. Ionic liquid acid-catalyzed Friedländer quinoline synthesis. Figure 25. Ionic liquid acid-catalyzed Friedländer quinoline synthesis. Citing its recent application to the preparation of heterocycles, Augustine and coworkers Citingexplored its the recent use applicationof peptide coupling to the preparation agent propylphosphonic of heterocycles, anhydride Augustine (T3P, and55, Figure coworkers 26) in exploredthe the useFriedländer of peptide reaction. coupling They agent were propylphosphonic gratified to find that anhydride a catalytic (T3P,loading55 ,of Figure T3P to 26 the) inreaction the Friedländer was reaction.sufficient They to were give very gratified high yields to find of thatdiversely-substituted a catalytic loading quinolines. of T3P Mechanistically, to the reaction they was propose sufficient to give veryT3P to high assist yields in the of initial diversely-substituted condensation of 32 quinolines.and 33, as well Mechanistically, as the subsequent they intramolecular propose T3P aldol to assist condensation to form the final product 56. in the initial condensation of 32 and 33, as well as the subsequent intramolecular aldol condensation to 56 form theMolecules final 2016 product, 21, 986 . 14 of 22

Molecules 2016, 21, 986 14 of 22

Figure 26. Friedländer quinoline synthesis via peptide coupling reagent. Figure 26. Friedländer quinoline synthesis via peptide coupling reagent. As a final exampleFigure 26. of Friedländera novel approach quinoline to synthesis the Friedländer via peptide quinoline coupling synthesis, reagent. Nageswar and Ascoworkers a ﬁnal example employed of a abiomimetic novel approach method toin thewhich Friedländer β-cyclodextrin quinoline acts in synthesis,enzyme-like Nageswar fashion, and coworkersperformingAs employed a final catalysis example a biomimeticof theof a reaction novel approach method within its into hydrophobic the which Friedländerβ-cyclodextrin cavity quinoline (Figure 27). actssynthesis, In in this enzyme-like way,Nageswar reactions and fashion, performingcoworkersinvolving catalysis hydrophobicemployed of the a substratesbiomimetic reaction withincan method be run its inwith hydrophobic which water β as-cyclodextrin the cavity sole solvent. (Figure acts Within 27 enzyme-like). a Incatalytic this way, amountfashion, reactions of β-CD, they obtained various quinoline-2,3-dicarboxylates 58 under neutral aqueous conditions in involvingperforming hydrophobic catalysis substratesof the reaction can within be run its with hydrophobic water as cavity the sole (Figure solvent. 27). In With this way, a catalytic reactions amount involvingexcellent hydrophobicyield, with a high substrates recovery can of be catalyst. run with water as the sole solvent. With a catalytic amount of β-CD, they obtained various quinoline-2,3-dicarboxylates 58 under neutral aqueous conditions in of β-CD, they obtained various quinoline-2,3-dicarboxylates 58 under neutral aqueous conditions in excellentexcellent yield, yield, with with a high a high recovery recovery of of catalyst. catalyst.

Figure 27. Friedländer quinoline synthesis via biomimetic catalysis.

5. Quinoline Synthesis via Novel Synthetic Routes Figure 27. Friedländer quinoline synthesis via biomimetic catalysis. Figure 27. Friedländer quinoline synthesis via biomimetic catalysis. 5.1. Electrophilic Cyclization 5. Quinoline Synthesis via Novel Synthetic Routes Larock and coworkers [41] described the first quinoline synthesis via electrophilic cyclization in 5.1.2010. Electrophilic Envisioning Cyclization a means of forming quinolines which contain functional groups that may not be amenable to any of the established methods, they investigated an electrophile-induced cyclization Larock and coworkers [41] described the first quinoline synthesis via electrophilic cyclization in reaction (Figure 28). The first step involved formation of propargylic arylamines 60 from anilines 1 and 2010. Envisioning a means of forming quinolines which contain functional groups that may not be haloalkynes 59, which were then treated with the electrophile-ICl, I2, Br2, PhSeBr, or ArSCl. It was amenable to any of the established methods, they investigated an electrophile-induced cyclization conjectured that the electrophile adds to the triple bond, which enhances the electrophilicity of the reaction (Figure 28). The first step involved formation of propargylic arylamines 60 from anilines 1 and alkyne, activating it toward attack by the aromatic ring. Through oxidation by air or the electrophile, haloalkynes 59, which were then treated with the electrophile-ICl, I2, Br2, PhSeBr, or ArSCl. It was the ring is aromatized, giving 3-halogen, selenium, or sulfur-substituted quinolines 61 in poor to very conjectured that the electrophile adds to the triple bond, which enhances the electrophilicity of the good yields. alkyne, activating it toward attack by the aromatic ring. Through oxidation by air or the electrophile, the ring is aromatized, giving 3-halogen, selenium, or sulfur-substituted quinolines 61 in poor to very good yields.

Molecules 2016, 21, 986 15 of 23

5. Quinoline Synthesis via Novel Synthetic Routes

5.1. Electrophilic Cyclization Larock and coworkers [41] described the ﬁrst quinoline synthesis via electrophilic cyclization in 2010. Envisioning a means of forming quinolines which contain functional groups that may not be amenable to any of the established methods, they investigated an electrophile-induced cyclization reaction (Figure 28). The ﬁrst step involved formation of propargylic arylamines 60 from anilines 1 and haloalkynes 59, which were then treated with the electrophile-ICl, I2, Br2, PhSeBr, or ArSCl. It was conjectured that the electrophile adds to the triple bond, which enhances the electrophilicity of the alkyne, activating it toward attack by the aromatic ring. Through oxidation by air or the electrophile, the ring is aromatized, giving 3-halogen, selenium, or sulfur-substituted quinolines 61 in poor to very Moleculesgood yields. 2016, 21, 986 15 of 22 Molecules 2016, 21, 986 15 of 22

FigureFigure 28. 28. QuinolineQuinoline synthesis synthesis via via electrophilic electrophilic cyclization of anilines and alkynes. Figure 28. Quinoline synthesis via electrophilic cyclization of anilines and alkynes. Xi et al. [42] reported alkyltriflate-mediated electrophilic cyclization of arylisothiocyanates 63 Xi et al. [42] reported alkyltriflate-mediated electrophilic cyclization of arylisothiocyanates 63 and alkynesXi et al. ( 62[42], Figure reported 29). alkyltriflate-mediated The reaction was presumed electrophilic to proceed cyclization through of anarylisothiocyanates alkyltriflate-formed 63 and alkynes (62, Figure 29). The reaction was presumed to proceed through an alkyltriflate-formed carbeniumand alkynes ion, (62 ,to Figure which 29). the The alkyne reaction adds was regioselec presumedtively. to proceedThe intermediate through an cyclizes, alkyltriflate-formed with triflate carbenium ion, to which the alkyne adds regioselectively. The intermediate cyclizes, with triflate assistingcarbenium in ion,the necessaryto which thedeprotonation alkyne adds and regioselec aromatization.tively. The In thisintermediate way, they cyclizes, were able with to triflateobtain assisting in the necessary deprotonation and aromatization. In this way, they were able to obtain variousassisting 2-thioquinolines in the necessary 64 deprotonation in good to excellent and aromatization. yield. In this way, they were able to obtain various 2-thioquinolines 6464 inin goodgood toto excellentexcellent yield.yield.

Figure 29. Alkyltriflate-mediated electrophilic cyclization of isothiocyanates with alkynes. Figure 29. Alkyltriflate-mediatedAlkyltriﬂate-mediated electrophilic cyclization of isothiocyanates with alkynes.alkynes. Danheiser and coworkers [43] developed an elaborate two-stage benzannulation/iodocyclization Danheiser and coworkers [43] developed an elaborate two-stage benzannulation/iodocyclization strategyDanheiser toward and highly coworkers substituted [43] developedquinolines an(Figure elaborate 30). The two-stage first stage benzannulation/iodocyclization involves the photochemical strategy toward highly substituted quinolines (Figure 30). The first stage involves the photochemical Wolffstrategy rearrangement toward highly of substituted α,β-unsaturated quinolines α-diazo (Figure ketones 30). 65 The toﬁrst transient stage involvesvinylketenes. the photochemical The ketene is Wolff rearrangement of α,β-unsaturated α-diazo ketones 65 to transient vinylketenes. The ketene is immediatelyWolff rearrangement involved of inα ,βa -unsaturatedregioselectiveα -diazo[2 + 2] ketones cycloaddition65 to transient with an vinylketenes. ynamide 66, Thegiving ketene an immediately involved in a regioselective [2 + 2] cycloaddition with an ynamide 66, giving an intermediateis immediately cyclobutenone. involved in After a regioselective four-electron [2electrocyclic + 2] cycloaddition cleavage of with the butene an ynamide ring, six-electron66, giving intermediate cyclobutenone. After four-electron electrocyclic cleavage of the butene ring, six-electron electrocyclican intermediate closure cyclobutenone. forms the aminophenol After four-electron ring (67). Upon electrocyclic introduction cleavage of an electrophile of the butene such as ring, I2, theelectrocyclic alkyne appendage closure forms performs the aminophenol electrophilic ring cyclization (67). Upon with introduction the aromatic of ring, an electrophile affording quinolines such as I2, withthe alkyne multiple appendage functionalities performs (68 ).electrophilic cyclization with the aromatic ring, affording quinolines with multiple functionalities (68).

Figure 30. Photochemical electrophilic cyclization to form highly functionalized quinolines. Figure 30. Photochemical electrophilic cyclization to form highly functionalized quinolines.

Molecules 2016, 21, 986 15 of 22

Figure 28. Quinoline synthesis via electrophilic cyclization of anilines and alkynes.

Xi et al. [42] reported alkyltriflate-mediated electrophilic cyclization of arylisothiocyanates 63 and alkynes (62, Figure 29). The reaction was presumed to proceed through an alkyltriflate-formed carbenium ion, to which the alkyne adds regioselectively. The intermediate cyclizes, with triflate assisting in the necessary deprotonation and aromatization. In this way, they were able to obtain various 2-thioquinolines 64 in good to excellent yield.

Figure 29. Alkyltriflate-mediated electrophilic cyclization of isothiocyanates with alkynes.

Danheiser and coworkers [43] developed an elaborate two-stage benzannulation/iodocyclization strategy toward highly substituted quinolines (Figure 30). The first stage involves the photochemical

WolffMolecules rearrangement2016, 21, 986 of α,β-unsaturated α-diazo ketones 65 to transient vinylketenes. The ketene16 of 23is immediately involved in a regioselective [2 + 2] cycloaddition with an ynamide 66, giving an intermediate cyclobutenone. After four-electron electrocyclic cleavage of the butene ring, six-electron electrocyclicsix-electron electrocyclicclosure forms closure the aminophenol forms the aminophenol ring (67). Upon ring (introduction67). Upon introduction of an electrophile of an electrophile such as I2, thesuch alkyne as I2, theappendage alkyne appendage performs electrophilic performs electrophilic cyclization cyclizationwith the aromatic with the ring, aromatic affording ring, quinolines affording withquinolines multiple with functionalities multiple functionalities (68). (68).

Figure 30. PhotochemicalPhotochemical electrophilic electrophilic cyclization to form highly functionalized quinolines. Molecules 2016, 21, 986 16 of 22

StopkaStopka and and Niggemann Niggemann [44] [44] recently recently disclosed the formation of substituted quinolines quinolines through through annulationannulation of of 2-azidobenzyl 2-azidobenzyl alcohols alcohols with with internal internal alkynes alkynes under under acidic acidic conditions conditions (Figure (Figure 31). The31). reactionThe reaction proceeds proceeds through through an acid-catalyzed an acid-catalyzed dehydration dehydration of alcohol of alcohol 69 to 69formto forma benzylic a benzylic cation. cation. This cationThis cation readily readily reacts reacts with withthe alkyne the alkyne 63, forming63, forming a vinyl a vinyl cation. cation. The nearby The nearby azide azide group group attacks attacks this cation,this cation, and with and withloss of loss N of2 and N2 deprotonation,and deprotonation, the quinoline the quinoline 70 is 70formed.is formed.

FigureFigure 31. 31. Acid-mediatedAcid-mediated cyclization cyclization of of arylazides arylazides with with alkynes.

Finally, Bräse and coworkers [45] described the synthesis of functionalized quinolines from Finally, Bräse and coworkers [45] described the synthesis of functionalized quinolines from sulfanyl ynamides 72 and electrophilically-activated aryl amides 71 under the influence of triflic sulfanyl ynamides 72 and electrophilically-activated aryl amides 71 under the inﬂuence of triﬂic anhydride and 2-chloropyridine (Figure 32). Inspired by the work of Movassaghi, who developed anhydride and 2-chloropyridine (Figure 32). Inspired by the work of Movassaghi, who developed this method to synthesize pyridine, pyrimidine, and β-carboline derivatives, the Bräse group applied this method to synthesize pyridine, pyrimidine, and β-carboline derivatives, the Bräse group applied this procedure to quinoline synthesis. They obtained many 4-sulfonylamino quinolines (73) in good this procedure to quinoline synthesis. They obtained many 4-sulfonylamino quinolines (73) in yield, which could then be easily converted to biologically useful amines by hydrolysis of the good yield, which could then be easily converted to biologically useful amines by hydrolysis of protecting group. the protecting group.

Figure 32. Electrophilic cyclization of aryl amides with sulfanyl ynamides.

5.2. Oxidative Cyclization As efforts to perform chemical syntheses in environmentally friendly ways has gained momentum in recent years, considerable interest has been given to aerobic oxidation as a method of bond activation. Lei and coworkers [46] applied this method to quinoline synthesis using simple primary amines (Figure 33). In fact, when 2-(aminomethyl)aniline 74 was reacted with various aryl ketones 33 under an oxygen atmosphere, the corresponding 2-aryl quinolines 75 were obtained in good yield.

Figure 33. Oxidative cyclization of aryl diamines with carbonyl compounds.

Molecules 2016, 21, 986 16 of 22 Molecules 2016, 21, 986 16 of 22 Stopka and Niggemann [44] recently disclosed the formation of substituted quinolines through annulationStopka of and 2-azidobenzyl Niggemann alcohols[44] recently with disclosed internal alkynes the formation under ofacidic substituted conditions quinolines (Figure through31). The annulationreaction proceeds of 2-azidobenzyl through an alcohols acid-catalyzed with internal dehydration alkynes of underalcohol acidic 69 to formconditions a benzylic (Figure cation. 31). ThisThe reactioncation readily proceeds reacts through with the an acid-catalyzedalkyne 63, forming dehydration a vinyl cation.of alcohol The 69 nearby to form azide a benzylic group cation.attacks This this cationcation, readilyand with reacts loss withof N 2the and alkyne deprotonation, 63, forming the a quinolinevinyl cation. 70 is The formed. nearby azide group attacks this cation, and with loss of N2 and deprotonation, the quinoline 70 is formed.

Figure 31. Acid-mediated cyclization of arylazides with alkynes. Figure 31. Acid-mediated cyclization of arylazides with alkynes. Finally, Bräse and coworkers [45] described the synthesis of functionalized quinolines from sulfanylFinally, ynamides Bräse and72 and coworkers electrophilically-activated [45] described the arylsynthesis amides of 71functionalized under the influence quinolines of triflicfrom sulfanylanhydride ynamides and 2-chloropyridine 72 and electrophilically-activated (Figure 32). Inspired arylby the amides work 71of underMovassaghi, the influence who developed of triflic anhydridethis method and to synthesize 2-chloropyridine pyridine, (Figure pyrimidine, 32). Inspir anded β-carboline by the work derivatives, of Movassaghi, the Bräse who group developed applied this methodprocedure to synthesizeto quinoline pyridine, synthesis. pyrimidine, They obtained and β -carbolinemany 4-sulfonylamino derivatives, the quinolines Bräse group (73) appliedin good thisyield, procedure which could to quinoline then be synthesis. easily converted They obtained to biologically many 4-sulfonylamino useful amines quinolines by hydrolysis (73) in of good the yield,protectingMolecules which2016 group., 21 could, 986 then be easily converted to biologically useful amines by hydrolysis of17 ofthe 23 protecting group.

Figure 32. Electrophilic cyclization of aryl amides with sulfanyl ynamides. FigureFigure 32. 32. ElectrophilicElectrophilic cyclization cyclization of of aryl amides with sulfanyl ynamides. 5.2. Oxidative Cyclization 5.2. Oxidative Oxidative Cyclization Cyclization As efforts to perform chemical syntheses in environmentally friendly ways has gained momentumAs effortsefforts in torecent to perform perform years, chemical considerable chemical syntheses syntheses interest in environmentally has in beenenvironmentally given friendly to aerobic waysfriendly oxidation has gainedways as ahas momentum method gained of momentumbondin recent activation. years, in recent considerable Lei andyears, coworkers interestconsiderable has [46] been interestapplied given has this to aerobicbeen method given oxidation to to quinoline aerobic as a method oxidation synthesis of bondas using a method activation. simple of bondprimaryLei and activation. coworkersamines (FigureLei [ 46and] 33). applied coworkers In fact, this when[46] method applied 2-(aminomethyl)aniline to quinoline this method synthesis to quinoline 74 usingwas reacted simplesynthesis with primary using various aminessimple aryl primaryketones(Figure 33 33amines). under In fact, (Figure an when oxygen 33). 2-(aminomethyl)aniline Inatmosphere, fact, when the2-(aminomethyl)aniline corresponding74 was reacted 2-aryl with 74 quinolines was various reacted aryl 75 withwere ketones variousobtained33 under aryl in ketonesgoodan oxygen yield. 33 atmosphere, under an oxygen the corresponding atmosphere, 2-arylthe corresponding quinolines 75 2-arylwere obtainedquinolines in 75 good were yield. obtained in good yield.

Figure 33. OxidativeOxidative cyclization of aryl di diaminesamines with carbonyl compounds. Molecules 2016, 21, 986Figure 33. Oxidative cyclization of aryl diamines with carbonyl compounds. 17 of 22

JiaJia et al. [47] [47] also used molecular oxygen, in in conjunction with with the radical cation salt tris(4-bromophenyl)aminium hexachloroantimonate (TBPA), to induce oxidation of sp3 C-H bonds tris(4-bromophenyl)aminium hexachloroantimonate (TBPA), to induce oxidation of sp C-H bonds adjacent to nitrogen (Figure 34).34). Reacting substituted N-cinnamylanilines under O 2 atmosphereatmosphere with a catalytic amountamount ofof thethe radical radical cation cation salt, salt, they they achieved achieved various various 2-aryl 2-aryl quinolines. quinolines. They They propose propose the theinitial initial step step of the of the mechanism mechanism to be to oxidation be oxidation of the of C-Hthe C-H bond bond next next to nitrogen to nitrogen by TBPA by TBPA and Oand2 to O give2 to givethe radical the radical intermediate, intermediate, which which is then is further then further oxidized oxidized to give to the give iminium the iminium ion. This ion. is then This attacked is then attackedby the aniline by the extruded aniline extruded from TBPA from via Michael-likeTBPA via Michael-like addition. After addition. cyclization, After cyclization, the aniline isthe extruded aniline isas extruded the ring aromatizes,as the ring aromatizes, giving the ﬁnal giving product. the final product.

Figure 34. Radical cation-catalyzed intramolecular oxidative cyclization. Figure 34. Radical cation-catalyzed intramolecular oxidative cyclization. Drawing on previous success forming functionalized indoles under aerobic oxidation and Drawing on previous success forming functionalized indoles under aerobic oxidation and palladium catalysis, Ghorai et al. [48] developed a metal-free cycloisomerization strategy of quinoline palladium catalysis, Ghorai et al. [48] developed a metal-free cycloisomerization strategy of quinoline synthesis, in which the oxidation is performed by dimethyl sulfoxide (DMSO) rather than molecular synthesis, in which the oxidation is performed by dimethyl sulfoxide (DMSO) rather than molecular oxygen (Figure 35). Reacting preformed ortho-allylanilines with a substoichiometric amount of oxygen (Figure 35). Reacting preformed ortho-allylanilines with a substoichiometric amount of potassium tert-butoxide in DMSO, they obtained diverse quinoline products, including 2-styryl potassium tert-butoxide in DMSO, they obtained diverse quinoline products, including 2-styryl derivatives for which a dearth of synthetic options exist. The mechanism is presumed to proceed derivatives for which a dearth of synthetic options exist. The mechanism is presumed to proceed through oxidation of 2-allylaniline via KOtBu and DMSO, then six-electron cyclization to give the through oxidation of 2-allylaniline via KOtBu and DMSO, then six-electron cyclization to give the dihydroquinoline. This is then oxidized to give the quinoline. dihydroquinoline. This is then oxidized to give the quinoline.

Figure 35. DMSO-mediated oxidative cycloisomerization.

5.3. Aza-Wittig Cascade Reactions The formation of iminophosphoranes, and their subsequent use in aza-Wittig reactions, has become a popular method of nitrogen-heterocycle formation. Shi et al. [49] reported a one-pot, L-proline-catalyzed aza-Wittig cascade reaction resulting in 2- and 3-substituted quinolines (Figure 36). The cascade begins with the Michael addition of the ketone 33 to the β-nitroolefin 80. A Staudinger reaction of the azide with triphenylphosphine forms the iminophosphorane, which then undergoes aza-Wittig to close the ring. The ring is aromatized with expulsion of nitromethane to give the product quinolines 81 in very good yield.

Molecules 2016, 21, 986 17 of 22

Jia et al. [47] also used molecular oxygen, in conjunction with the radical cation salt tris(4-bromophenyl)aminium hexachloroantimonate (TBPA), to induce oxidation of sp3 C-H bonds adjacent to nitrogen (Figure 34). Reacting substituted N-cinnamylanilines under O2 atmosphere with a catalytic amount of the radical cation salt, they achieved various 2-aryl quinolines. They propose the initial step of the mechanism to be oxidation of the C-H bond next to nitrogen by TBPA and O2 to give the radical intermediate, which is then further oxidized to give the iminium ion. This is then attacked by the aniline extruded from TBPA via Michael-like addition. After cyclization, the aniline is extruded as the ring aromatizes, giving the final product.

Figure 34. Radical cation-catalyzed intramolecular oxidative cyclization.

Drawing on previous success forming functionalized indoles under aerobic oxidation and palladium catalysis, Ghorai et al. [48] developed a metal-free cycloisomerization strategy of quinoline synthesis, in which the oxidation is performed by dimethyl sulfoxide (DMSO) rather than molecular oxygen (Figure 35). Reacting preformed ortho-allylanilines with a substoichiometric amount of potassium tert-butoxide in DMSO, they obtained diverse quinoline products, including 2-styryl derivatives for which a dearth of synthetic options exist. The mechanism is presumed to proceed t throughMolecules 2016 oxidation, 21, 986 of 2-allylaniline via KO Bu and DMSO, then six-electron cyclization to give18 ofthe 23 dihydroquinoline. This is then oxidized to give the quinoline.

Figure 35. DMSO-mediated oxidative cycloisomerization. Figure 35. DMSO-mediated oxidative cycloisomerization.

5.3. Aza-Wittig Cascade Reactions 5.3. Aza-Wittig Cascade Reactions The formation of iminophosphoranes, and their subsequent use in aza-Wittig reactions, has The formation of iminophosphoranes, and their subsequent use in aza-Wittig reactions, has become a popular method of nitrogen-heterocycle formation. Shi et al. [49] reported a one-pot, become a popular method of nitrogen-heterocycle formation. Shi et al. [49] reported a one-pot, L-proline-catalyzed aza-Wittig cascade reaction resulting in 2- and 3-substituted quinolines (Figure 36). L-proline-catalyzed aza-Wittig cascade reaction resulting in 2- and 3-substituted quinolines (Figure 36). The cascade begins with the Michael addition of the ketone 33 to the β-nitroolefin 80. A Staudinger The cascade begins with the Michael addition of the ketone 33 to the β-nitrooleﬁn 80. A Staudinger reaction of the azide with triphenylphosphine forms the iminophosphorane, which then undergoes reaction of the azide with triphenylphosphine forms the iminophosphorane, which then undergoes aza-Wittig to close the ring. The ring is aromatized with expulsion of nitromethane to give the aza-Wittig to close the ring. The ring is aromatized with expulsion of nitromethane to give the product product quinolines 81 in very good yield. quinolinesMolecules 201681, 21in, 986 very good yield. 18 of 22

NO 2 20 mol% L-proline R3 O NEt3, PPh3 + R R 3 N3 2 CH2Cl2, r.t. N R2 R1 15 examples, 65-94% yield. R1 80 33 81

L-proline -CH NO NEt3 3 2 NO NO 2 2 NO 2 R PPh R 3 3 3 cyclization R3

COR 2 COR 2 N N -Ph3PO 3 N R2 R1 R1 R1 PPh3

Figure 36. Base-catalyzed aza-Wittig cyclization of quinoines.

He and coworkers [50] took a similar approach with a cascade reaction of ortho-azidobenaldehyde He and coworkers [50] took a similar approach with a cascade reaction of and various carbonyl and dicarbonyl compounds (Figure 37). Through a Knoevenagel/Staudinger/ ortho-azidobenaldehyde and various carbonyl and dicarbonyl compounds (Figure 37). Through a aza-Wittig cascade, this group obtained quinolines in which the 2- and 3-substituents could be altered Knoevenagel/Staudinger/aza-Wittig cascade, this group obtained quinolines in which the 2- and based on the annulation partner and reaction conditions used. Reacting 2-azidobenzaldehyde 82 with 3-substituents could be altered based on the annulation partner and reaction conditions used. mono-carbonyl compounds 33, disubstituted quinolines 83 were produced in very good yield. On Reacting 2-azidobenzaldehyde 82 with mono-carbonyl compounds 33, disubstituted quinolines 83 the other hand, 2-carbonylquinolines 85 were obtained in good yield by reaction with 2,3-carbonyl were produced in very good yield. On the other hand, 2-carbonylquinolines 85 were obtained in good compounds 84, while 3-carbonylquinolines 87 were obtained by reaction with 1,3-carbonyl yield by reaction with 2,3-carbonyl compounds 84, while 3-carbonylquinolines 87 were obtained by compounds 86. reaction with 1,3-carbonyl compounds 86. O

R1 R2 R2 84 O R1 cat. piperidine, PPh3 N THF, Δ O O 85 O 2 examples, 80-85% yield. R2 R R1 2 33

cat. piperidine, PPh N R1 3 N3 THF, Δ O O 83 10 examples, 85-92% yield. 82 O R1 R2 86 R2

cat. piperidine, PPh3 N R1 THF, Δ 4 examples, 80-88% yield. 87

Figure 37. Aza-Wittig cascade reaction of azidobenzaldehyde with mono- and dicarbonyl compounds.

5.4. Other (Radical-Promoted, Cycloaddition, I2 Catalyzed) An alternative method of quinoline synthesis involves radical-promoted cyclization of arylamine precursors. Yu and coworkers [51] synthesized quinolines substituted at the 3-position via an N-bromosuccinamide-mediated radical reaction (Figure 38). They proposed the mechanism to begin with the visible light-promoted formation of bromine radical from NBS. This radical reacts with the C-H adjacent to the azide on propenoate 88, and through extrusion of N2, the radical imine cyclizing with the aryl ring. Oxidation rearomatizes the ring, giving the desired quinoline products 89 in fair to good yield.

Molecules 2016, 21, 986 18 of 22

NO 2 20 mol% L-proline R3 O NEt3, PPh3 + R R 3 N3 2 CH2Cl2, r.t. N R2 R1 15 examples, 65-94% yield. R1 80 33 81

L-proline -CH NO NEt3 3 2 NO NO 2 2 NO 2 R PPh R 3 3 3 cyclization R3

COR 2 COR 2 N N -Ph3PO 3 N R2 R1 R1 R1 PPh3 Figure 36. Base-catalyzed aza-Wittig cyclization of quinoines.

He and coworkers [50] took a similar approach with a cascade reaction of ortho-azidobenaldehyde and various carbonyl and dicarbonyl compounds (Figure 37). Through a Knoevenagel/Staudinger/ aza-Wittig cascade, this group obtained quinolines in which the 2- and 3-substituents could be altered based on the annulation partner and reaction conditions used. Reacting 2-azidobenzaldehyde 82 with mono-carbonyl compounds 33, disubstituted quinolines 83 were produced in very good yield. On the other hand, 2-carbonylquinolines 85 were obtained in good yield by reaction with 2,3-carbonyl compoundsMolecules 2016, 2184, 986, while 3-carbonylquinolines 87 were obtained by reaction with 1,3-carbonyl19 of 23 compounds 86.

R1 R2 R2 84 O R1 cat. piperidine, PPh3 N THF, Δ O O 85 O 2 examples, 80-85% yield. R2 R R1 2 33

cat. piperidine, PPh N R1 3 N3 THF, Δ O O 83 10 examples, 85-92% yield. 82 O R1 R2 86 R2

cat. piperidine, PPh3 N R1 THF, Δ 4 examples, 80-88% yield. 87

FigureFigure 37. 37. Aza-WittigAza-Wittig cascade cascade reaction reaction of of azidobenzalde azidobenzaldehydehyde with mono- andand dicarbonyldicarbonyl compounds.compounds.

5.4. Other (Radical-Promoted, Cycloaddition, I2 Catalyzed)Catalyzed) An alternative method of quinoline synthesis invo involveslves radical-promoted cy cyclizationclization of arylamine precursors. Yu Yu and and coworkers coworkers [51] [51] synthesized synthesized quinolines quinolines substituted substituted at at the 3-position via an N-bromosuccinamide-mediated radical reaction (Figure(Figure 3838).). They proposed the mechanism to begin with the visible light-promoted formation of bromine radical from NBS. This radical reacts with the 2 C-H adjacent to the azide on propenoate 88, and throughthrough extrusionextrusion ofof NN2, the radical imine cyclizing with the arylaryl ring.ring. OxidationOxidation rearomatizesrearomatizes the the ring, ring, giving giving the the desired desired quinoline quinoline products products89 89in in fair fair to to good yield. Moleculesgood yield. 2016, 21, 986 19 of 22

CO2Me CO Me NBS 2

ν N3 CH2Cl2, r.t., h N R 1 88 11 examples, 30-82% yield. R1 89

hν NBS Br oxidation

CO Me 2 CO2Me CO2Me

N3 N cyclization -N2 N R1 R H 1 R1

Figure 38. NBS-mediated radical cyclization to form 3-substituted quinolines.

Huang et al. [52] developed a divergent method of I2-catalyzed quinoline synthesis from enamides Huang et al. [52] developed a divergent method of I -catalyzed quinoline synthesis from enamides and imines (Figure 39). The reaction is initiated by ortho2-iodination of the aryl imine 90, followed by and imines (Figure 39). The reaction is initiated by ortho-iodination of the aryl imine 90, followed by insertion of the enamide 91 into the newly formed C-I bond. Cyclization and loss of acetamide then insertion of the enamide 91 into the newly formed C-I bond. Cyclization and loss of acetamide then form the diaryl quinoline 92. form the diaryl quinoline 92.

Figure 39. Iodine-catalyzed synthesis of diarylquinolines from enamides and imines.

Verma et al. [53] described a chemo- and regioselective [4 + 2]-cycloaddition of alkynes with in situ-generated azadienes (Figure 40). The mechanism is presumed to initiate with the DMSO/KOH- promoted dehydration of 2-aminobenzyl alcohol 93, forming the azadiene which was isolated under control experiments. The azadiene then cyclizes with the alkyne 63, and the quinoline 94 is formed upon oxidation.

Figure 40. [4 + 2] Cycloaddition of azadienes with internal alkynes.

Molecules 2016, 21, 986 19 of 22 Molecules 2016, 21, 986 19 of 22 CO2Me CO Me NBS 2 CO2Me CO Me NBS 2 ν N3 CH2Cl2, r.t., h N R1 N 11 examples, 30-82%ν yield. R 88 3 CH2Cl2, r.t., h 1 89 N R 1 88 11 examples, 30-82% yield. R1 89 hν NBS ν Br h oxidation NBS Br oxidation

CO Me 2 CO2Me CO2Me CO Me 2 CO2Me CO2Me N3 -N N cyclization N R 2 H 1 N3 R1 N cyclization -N2 R1 N R1 R H 1 R1 Figure 38. NBS-mediated radical cyclization to form 3-substituted quinolines. Figure 38. NBS-mediated radical cyclization to form 3-substituted quinolines.

Huang et al. [52] developed a divergent method of I2-catalyzed quinoline synthesis from enamides and iminesHuang (Figureet al. [52] 39). developed The reaction a divergent is initiated method by orthoof I2-catalyzed-iodination quinoline of the aryl sy nthesisimine 90 from, followed enamides by and imines (Figure 39). The reaction is initiated by ortho-iodination of the aryl imine 90, followed by Moleculesinsertion2016 of, the21, 986 enamide 91 into the newly formed C-I bond. Cyclization and loss of acetamide20 then of 23 insertionform the diarylof the enamidequinoline 91 92 into. the newly formed C-I bond. Cyclization and loss of acetamide then form the diaryl quinoline 92.

Figure 39. Iodine-catalyzed synthesis of diarylquinolines from enamides and imines.imines. Figure 39. Iodine-catalyzed synthesis of diarylquinolines from enamides and imines. Verma et al. [53] described a chemo- and regioselective [4 + 2]-cycloaddition of alkynes with in Verma et al. [53] described a chemo- and regioselective [4 + 2]-cycloaddition of alkynes situ-generatedVerma et al. azadienes [53] described (Figure a 40).chemo- The andmechanism regioselective is presumed [4 + 2]-cycloaddition to initiate with of the alkynes DMSO/KOH- with in with in situ-generated azadienes (Figure 40). The mechanism is presumed to initiate with the situ-generatedpromoted dehydration azadienes of (Figure 2-aminobenzyl 40). The alcoholmechanism 93, forming is presumed the azadiene to initiate which with was the isolatedDMSO/KOH- under DMSO/KOH-promoted dehydration of 2-aminobenzyl alcohol 93, forming the azadiene which was promotedcontrol experiments. dehydration The of 2-aminobenzylazadiene then cyclizes alcohol with93, forming the alkyne the azadiene 63, and the which quinoline was isolated 94 is formed under isolated under control experiments. The azadiene then cyclizes with the alkyne 63, and the quinoline controlupon oxidation. experiments. The azadiene then cyclizes with the alkyne 63, and the quinoline 94 is formed upon94 is formedoxidation. upon oxidation.

Figure 40. [4 + 2] Cycloaddition of azadienes with internal alkynes. Figure 40. [4 + 2] Cycloaddition of azadienes with internal alkynes. Figure 40. [4 + 2] Cycloaddition of azadienes with internal alkynes. Molecules 2016, 21, 986 20 of 22

Finally,Finally, a a very very recent recent contribution contribution from from Tang Tang et et al. al [. 54[54]] describes describes the the synthesis synthesis of of 3-arylsulfonylquinolines3-arylsulfonylquinolines95 95from fromN -propargylN-propargyl aromatic aromatic amines amines96 96and and arylsulfonylhydrazides arylsulfonylhydrazides97 97 (Figure(Figure 41 ).41). The The oxidative oxidative cyclization cyclization reaction reaction is is promoted promoted by bytert tert-butyl-butyl hydroperoxide hydroperoxide (TBHP) (TBHP) and and a singlea single electron electron mechanistic mechanistic pathway pathway is is proposed proposed to to deliver deliver the the products products in in good good to to excellent excellent yields. yields.

Figure 41. Oxidative cyclization to provide 3-arylsulfonylquinolines Figure 41. Oxidative cyclization to provide 3-arylsulfonylquinolines.

6. Conclusions The quinoline ring system is ubiquitous in the fields of medicinal and industrial chemistry. Because of the broad range of uses for this scaffold, methods aimed at improving the efficiency and versatility of quinoline synthesis have been studied for over a century. Several recent developments in this field involve modifications to established methods such as the Skraup, Doebner–Von Miller, and Friedländer synthetic routes, including the use of ionic liquids, various catalysts, and novel reagents. In addition, examples of innovative processes toward these molecules include oxidative and radical-promoted cyclizations, cascade reactions, and electrophilic annulations. The scope of reactivity presented in this review indicates the availability of efficient, practical, metal-free synthetic routes toward quinolines with nearly any substitution pattern desired.

Acknowledgments: We thank the University of Denver for supporting this research.

Author Contributions: Ginelle A. Ramann collected references and wrote the manuscript. Bryan J. Cowen conceived the topic and edited the manuscript.

Conflicts of Interest: The authors declare no conflict of interest.

References

1. Meldola, R. Coal and What We Get from It: A Romance of Applied Science; Society for Promoting Christian Knowledge: London, UK, 1913. 2. Achan, J.; Talisuna, A.O.; Erhart, A.; Yeka, A.; Tibenderana, J.K.; Baliraine, F.N.; Rosenthal; P.J.; D'Alessandro, U. Quinine, an old anti-malarial drug in a modern world: Role in the treatment of malaria. Malar J. 2011, 10, 144.

3. Chanda, T.; Verma, R.K.; Singh, M.S. InCl3-driven regioselective synthesis of functionalized/annulated quinolines: Scope and limitations. Chem. Asian J. 2012, 7, 778−787. 4. Evans, B.E.; Rittle, K.E.; Bock, M.G.; DiPardo, R.M.; Freidinger, R.M.; Whitter, W.L.; Lundell, G.F.; Veber, D.F.; Anderson, P.S.; Chang, R.S.L.; et al. Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists. J. Med. Chem. 1988, 31, 2235−2246. 5. Bräse, S. Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation; Royal Society of Chemistry: London, UK, 2015. 6. Denmark, S.E.; Venkatraman, S. On the Mechanism of the Skraup−Doebner−Von Miller Quinoline Synthesis. J. Org. Chem. 2006, 71, 1668−1676. 7. Li, J.J. Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications; Springer International Publishing: Cham, Switzerland, 2014. 8. Povarov, L.S.; Grigos, V.I.; Mikhailov, B.M. Reaction of benzylideneaniline with some unsaturated compounds. Bull. Acad. Sci. USSR 1963, 12, 1878−1880. 9. Bharate, J.B.; Vishwakarma, R.A.; Bharate, S.B. Metal-free domino one-pot protocols for quinoline synthesis. RSC Adv. 2015, 5, 42020−42053.

Molecules 2016, 21, 986 21 of 23

6. Conclusions The quinoline ring system is ubiquitous in the fields of medicinal and industrial chemistry. Because of the broad range of uses for this scaffold, methods aimed at improving the efficiency and versatility of quinoline synthesis have been studied for over a century. Several recent developments in this field involve modifications to established methods such as the Skraup, Doebner–Von Miller, and Friedländer synthetic routes, including the use of ionic liquids, various catalysts, and novel reagents. In addition, examples of innovative processes toward these molecules include oxidative and radical-promoted cyclizations, cascade reactions, and electrophilic annulations. The scope of reactivity presented in this review indicates the availability of efficient, practical, metal-free synthetic routes toward quinolines with nearly any substitution pattern desired.

Acknowledgments: We thank the University of Denver for supporting this research. Author Contributions: Ginelle A. Ramann collected references and wrote the manuscript. Bryan J. Cowen conceived the topic and edited the manuscript. Conﬂicts of Interest: The authors declare no conﬂict of interest.

References

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