Synthesis of Quinolines: A Green Perspective - ACS Publications

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Synthesis of Quinolines: A Green Perspective Vasco Figueiredo Batista, Diana C. G. A. Pinto, and Artur M. S. Silva ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.6b01010 • Publication Date (Web): 28 Jun 2016 Downloaded from http://pubs.acs.org on June 28, 2016

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ACS Sustainable Chemistry & Engineering

Synthesis of Quinolines: A Green Perspective Vasco F. Batista, Diana C. G. A. Pinto,* Artur M. S. Silva Department of Chemistry & QOPNA, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal

ABSTRACT: The quinoline scaffold is present in a vast number of natural compounds and pharmacologically active substances, comprising a significant segment of the pharmaceutical market. The classical methods for the synthesis of this heterocyclic skeleton require the use of expensive starting materials and high temperature conditions. Chemists play a fundamental role in the construction of a sustainable future through the pursuit of greener chemical processes. As so, the development of new synthetic methods using more efficient energy sources and less hazardous solvents as well as renewable and eco-friendly catalysts to attain the quinoline scaffold can provide significant environmental and economic advantages. This review unveils green methods used in the synthesis of quinolones. Important green metrics are calculated for each proposed method and the statistical analysis allowed us to propose the best approaches for further investigation. The applied research is eventually unveiling the full potential of Friedländer and/or multicomponent reactions, to improve atom economy. KEYWORDS: Quinolines, Green chemistry, Green metrics, Alternative solvents, Microwave irradiation,

Atom

economy,

E-factor,

Effective

mass

yield,

Friedländer

reaction,

Multicomponent reactions.

ACS Paragon Plus Environment

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INTRODUCTION Quinoline was first discovered by Friedlieb Rouge in 1834, as a colourless hygroscopic liquid obtained by the distillation of coal tar. However, its structure, comprised of a rigid heterocyclic core of benzene ortho-fused with a pyridine ring (1), was only unveiled in 1871 as Dewar observed the chemical similarity between pyridine and quinoline.1,2 Since its discovery, the main source of commercial quinoline has remained coal tar, though several reactions have been developed for its synthesis.3,4 Furthermore, numerous derivatives presenting important biological activities have been extracted from plants and/or synthetized.5,6 It was considered that the synthesis of quinolin-2(1H)-one (2) and quinolin-4(1H)-one (3) derivatives falls within the scope of this paper due to their prompt tautomerism to 2-hydroxyquinolines and 4-hydroxyquinolines (Figure 1).

Figure 1. The quinoline scaffold, main derivatives and respective numbering system. To this day extensive libraries of quinoline derivatives are reported, presenting both broad industrial and medicinal applications. Quinolinic acid is a precursor in the synthesis of pesticides and herbicides and 8-hydroxyquinoline is employed in liquid bandages.3 Likewise, several derivatives having complex structures have been investigated for the use in OLED’s and in nanoand chemo-sensors.7,8 Besides, quinoline derivatives present important pharmacological applications due to their significant antimalarial, anti-inflammatory, antitumor, antibacterial and antiviral activities.9 Significant anticonvulsant10 and cardiovascular11 activities, as well as various central nervous system effects12 have also been reported.


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Several 4-aminoquinolines have followed the success of chloroquine (4) as powerful antimalarial drugs and some bisquinolines and ferrocenyl-chloroquine conjugates have been studied for the treatment of resistant strains.13–15 Moreover, N-(1-benzoyl)quinolin-4(1H)-one-2carboxylates (5) have shown remarkable potential as anti-inflammatory drugs with reduced side effects, through the selective inhibition of cyclooxigenase-2;16 more structure complex quinolines, as topotecan® (6) and irinotecan® (7), are already used in the treatment of ovarian and lung cancer, respectively. Quinolin-4(1H)-ones have been extensively developed for the treatment of bacterial infections, being some of the more potent 6-fluoroquinolin-4(1H)-ones and its 3-carboxylic derivatives, as ciprofloxacin® (8) and levofloxacin® (9), successfully marketed as broad spectrum antibiotics for the treatment of multi-resistant strains (Figure 2).17 It is worth to mention that some 6nitroquinolin-4(1H)-one-3-carboxylic acids have also proven remarkable in the treatment of tuberculosis.18

Figure 2. Structure of quinoline derivatives with important pharmacological properties


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The quinoline structural motif is readily available through a number of classical synthetic routes and from commercially available reagents. The Friedländer synthetic method (A) from ortho-aminoacetophenones (10) and the Skraup (B), Combes (D) and Doebner-Miller (F) syntheses from anilines (11), as well as its adaptations, are good examples. Moreover, the Conrad-Limpach (C), Gould-Jacobs (E) and Camps (G) routes for the synthesis of quinolones are widely used methods (Scheme 1). Still, all classical methods have similar disadvantages, requiring highly acidic and/or oxidizing media, high temperatures and long reaction times. Moreover, most of these synthetic routes present selectivity problems with meta-substituted substrates and its versatility is limited by the reactivity of the methylenic carbon involved in the aldol reaction.19 Although efficient and versatile, classical routes towards the synthesis of quinolines present serious environmental concerns as most synthetic routes use great excess of a reagents and produce a significant amount of toxic waste.


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Scheme 1. Main synthetic routes towards the quinoline scaffold Chemical processes are a vital part in the production of manufactured products. From these, the synthesis of drugs presents the highest E-factors, typically ranging from 25-100. In fact, a large strain is put both the environment, through the consumption of natural resources and the generation of large amounts of toxic waste, and the financial structure of pharmaceutical companies, due to increasing regulations in waste treatment and disposal.20


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The discovery of new and green approaches towards the synthesis of chemical entities can have a significant impact in the ecological footprint of the chemical industry, reducing at the same time the costs associated with the use of high temperature and treatment of produced waste. As so, increasing focus and funding has been put in green chemistry.21–23 In the following section a small review of the referred approaches is given, subdivided in two main levels: the use of alternative and more efficient energy sources and substitution of hazardous solvents towards more eco-friendly reaction media. Likewise, the use of alternative and renewable catalysts is mentioned. Statements regarding the environmental impact are generally supported with common green metrics. GREEN SYNTHESIS OF QUINOLINES AND QUINOLINE DERIVATIVES A) Microwave irradiation Solvent-free reactions. Several methods have been developed for the synthesis of quinolines and quinolones through microwave irradiation in neat conditions. Muscia et al. described a procedure towards the Friedländer synthesis of 2,3,4-trisubstituted quinolines (14) under acid catalysis, reporting yields above 50% in 6 to 12 minutes reaction time (Scheme 2. – route 1).24 Though mentioned otherwise, HCl is used as a stoichiometric catalyst, and a great excess of the ketone reagent is required. As so, the atomic efficiency of this synthesis is still a major setback towards its application. An alternative method was presented by Park and Kwon in which a green catalyst, diphenylphospate (DPP), was used to prepare oligoquinolines under 12 minutes of microwave irradiation, with yields depending on the complexity of the final product (Scheme 2 - route 2).25 A more appealing catalyst of SiO2 nanoparticles (NPs) showed higher catalytic activity than other oxides and was further developed to allow the synthesis of 2,3-disubstituted 4-


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phenylquinolines under 10 minutes and excellent yields (Scheme 2 – route 3). The low-cost, biocompatibility and easy removal from the reaction medium can be highlighted as advantages to the use of this catalyst.26

Scheme 2 Furthermore, Chaudhuri and Hussain reported the use of SnCl2 as an efficient oxidant toward the synthesis of 2,3-disubstituted quinolines (16) from ortho-nitrobenzaldehyde (15) and enolisable ketones (13) with great yields (Scheme 3), therefore eliminating the need for the preparation of the normal ortho-amino reagent.27

Scheme 3 Multicomponent reactions (MCR) stand as a newer approach towards an environmentally friendly synthesis, allowing the fast production of structure complex products from simple reagents without further purification need. The synthesis of 2,3-disubstituted quinolines (19) from aniline (11), aldehydes (17) and acetylene derivatives (18) is a great example, catalysed by either rare-earth metal catalysts28 or triflates.29 From these, it was assessed that YCl3 (Scheme 4 -


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route 1) and In(OTf)3 (Scheme 4 – route 2) have the best catalytic activity. Both catalysts originated excellent yields and YCl3 showed no loss in catalytic activity after six cycles.

Scheme 4 Other MCR techniques have been presented employing aniline, aldehydes and either alcohols, ketones or esters. Mura et al. reported the synthesis of 2,3-disubstitued quinolines using both a ruthenium oxidant and acid catalyst, trifluoroacetic acid (TFA), under microwave irradiation for three hours.30 The use of strong acids and long irradiation time surpasses the advantages of substituting the aldehyde for an alcohol reagent through a hydrogen-transfer methodology. Moreover, a catalyst-free method to synthesise 7-chloro-6-fluoro-2-phenylquinoline-4carboxylic acid (23) was recently reported from an aniline derivative (11), benzaldehyde (20) and pyruvic acid (21) with excellent yields.31 The fast, efficient and green reaction, and the rather accessible reagents make this synthesis appealing for further exploitation. Moreover, a TiO2 nanopowder catalyst has presented good photocatalytic activity towards a similar synthesis, providing a fast approach to 2-hydroxyquinolines (24) with 65-85% yield (Scheme 5).32 Though easy catalyst separation could be achieved through filtration, no recyclability study was mentioned.


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Scheme 5 Finally, various studies described alternative methods for the Conrad-Limpach synthesis of quinolones. First, Rivkin used activated malonates, as improved enolisable compounds, to prepare N,6,7-trisubstituted 4-hydroxy-3-phenylquinolin-2(1H)-ones with excellent yields.33 This synthesis provides safer conditions due to the reduction of the inner pressure. However, the synthesis of the referred reagent, its further treatment and disposal still carries some environmental concerns. Other methods involved either strong acid or base catalysis with paratoluenesulfonic acid (PTSA),34 polyphosphoric acid (PPA)35 or NaH.36 Sapkal et al. reported a heterogeneous catalysts for the Conrad-Limpach method, developing the synthesis of 2-methylquinolin-4(1H)-ones using NaHSO4 supported in SiO2, with 87-93% overall yield and short reaction times.37 Moreover, a catalyst-free method has been reported for the synthesis of 4-hydroxyquinolin-2(1H)-ones. Disadvantages of this last method include the need of an excess of malonate (2:1) and extremely high temperatures of 290ºC, resulting in large energy consumption.38 Ethanol. A synthesis of 2-phenylquinolines (27) from 2-aminobenzyl alcohol (25) and acetophenone (26) with a catalytic amount of sodium hydroxide and stoichiometric amount of T3P®-DMSO as oxidant was reported by Bharathkuman et al. and presented excellent yields (Scheme 6).39 The low reaction temperature and the use of an environmentally friendly oxidant,


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non-toxic and safe to handle, stand as the main advantages of this technique, but the high cost of T3P® may halt further investigation.

Scheme 6 Reactions in ionic liquids. Two procedures were found regarding the use of ionic liquids (IL) in the microwave assisted synthesis of quinolines. Bharate et al. reported the catalyst-free synthesis of 3-phenylquinolines from aniline derivatives and phenylacetaldehyde with average yields. The formation of mixtures of 2- and 2,3-disubstituted quinolines reduces the overall atom economy and introduces an additional purification step.40 Additionally, an article reports the Skraup synthesis of 6,8-disubstituted 2-arylquinolines in [Bmim][BF4] under 100 seconds of MW irradiation with yields above 70%.41 However, the synthesis of the used IL required complex reagents, high temperatures and the addition of concentrated acid. Furthermore, no recyclability study has been reported and as so the actual environmental impact of this synthesis can be greater than expected. Others. Additional methods have been presented toward the microwave-assisted synthesis of quinolines. Two MCR’s with polyoxometalate (POM)42 or palladium catalyst/CuI43 catalysis were reported, presenting good yields and flexibility of substituents in the benzene ring. Moreover, the need of dry solvents in palladium catalysis and the recyclability of the POM catalyst favour the first method in a green perspective.


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A synthesis of quinolin-4(1H)-ones from aniline and ethyl acetoacetate in acetic acid and Ph2O was also mentioned with good yields. Unfortunately, it is stated that the use of activated anilines leads to the formation of N,N’-dialkylureas, therefore limiting the scope of this synthesis.44 A notable and versatile base catalysed Pfitzinger synthesis of quinoline-2,4-dicarboxylic acids (30), from isatin (28) and sodium pyruvate (29), in water, was reported with excellent yields (Scheme 7).45 This method covers most milestones of green chemistry, with an efficient energy supply, green solvent and reagents easily obtained from natural sources. An additional reaction in water was presented by Saggadi et al. for the batch synthesis of quinoline from aniline and glycerol, at high temperatures and pressures, with average yields.46 The low atom economy of this synthesis as well as the large energy consumption and complicated reactor conditions make it unattractive for further study.

Scheme 7 B) Mild temperatures Solvent-free reactions. Two solvent-free methods are here presented for the mild temperature Friedländer synthesis of quinolines. A silica and molecular iodine catalyst has delivered good yields in the synthesis of various 2,3,4-trisubstituted quinolines in less than 12 hours, at 60ºC.47 Besides, Jida and Deprez demonstrated the high yield and great versatility of a similar synthesis using T3P® as a stoichiometric catalyst, at mild temperatures (60ºC) and short reactions times (30-60 minutes).48 This method presents great environmental features through the high yield obtained, the use of easily obtainable reagents and environmental friendly catalysts.


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Nevertheless, the high costs of T3P® may be inconvenient in comparison with other methods described. Reactions in ionic liquids. Sarma and Prajatapi presented a synthesis of 2,4-disubstituted quinolines from ortho-aminoacetophenones and nitriles, in an IL with Zn(OTf)2 as catalyst. Moreover, excellent yields were obtained with a catalytic amount of triflate (1%) and only a small amount of activity was loss after four cycles of solvent reuse.49 In the same study, an optimization study of yield regarding the use of different ILs was presented, choosing [hmim][PF6] as the solvent with best catalytic activity. However, this study does not test all the possible ILs combinations and, as so, it reported a more thorough work with the same reaction trying to achieve high yields using [hmim][BF4] as solvent.50 Furthermore, the direct use of enolisable ketones excludes the need of a catalyst and the reaction proceeds with only a small increase of temperature and reaction time (3-6 h). Finally, an interesting study highlighted the synthesis of 4-arylquinoline-3-carbonitrile analogues in a catalyst-free MCR. High yields are reported for a great variety of substituents at low temperatures (50ºC), but the further need of a reduction reaction in order to reach the quinoline scaffold complicates the process.51 Reactions in supercritical solvents. One study described the use of supercritical (SC) CO2 for the synthesis of 3,4-dihydroquinolin-1(2H)-ones (32) (Scheme 8).52 Reductive cyclization of 3(2-nitrophenyl)acrylic acids (31) with a stoichiometric amount of zinc dust and ammonium formate was performed with good yields at mild temperatures. Besides, liquid reagents were adsorbed in silica gel, an essential part in the progress of the reaction. Short reaction time is an encouraging factor but the extra time involved in the pressure introduction must be considered. Moreover, the primary reagent presents additional complexity to most methods already


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described, therefore putting in question the actual cost and environmental impact of the synthesis.

Scheme 8 Ethanol. Numerous methods have been developed for the Friedländer synthesis of quinolines in ethanol at mild temperatures, through the use of alternative catalysts such as Amberlyst-15,53 NaAuCl4,54 ZrO2/Fe3O4 magnetic nanoparticles (MNPs)55 or alkoxyamine linkers.56 All methods present great yields and good versatility of functional groups at C-2, C-3 and C-4. Moreover, the use of magnetic nanoparticles allowed a fast synthesis and easy removal of catalyst with no loss of catalytic activity after four cycles. Sadly, the gold complex described cannot be readily separated from the reaction media, requiring flash chromatograph. Besides, the use of alkoxyamine linker required a two-pot and longer time reaction. McNaughton and Miller devised a SnCl2/ZnCl2 catalyst for the synthesis of 2,3-disubstituted quinolines in ethanol from easily obtainable ortho-nitroaldehydes.57 Nevertheless, this method does require a water-free environment. In 2012, a rather unique method was published for the Friedländer reaction in lactic acid with a slight ketone excess.58 The synthesis proceeded with great yields in short reaction times, and treatment of reaction medium involved the formation of sodium lactate, a non-toxic species with known food applications. Finally, two relevant disclosed distinct MCR methods towards the quinoline synthesis in refluxing ethanol have been disclosed. The synthesis of 2-amino-4-phenylquinoline-3-


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carbonitrile catalysed by MgO nanoparticles presented excellent yields in less than 30 minutes reaction time.59 Nevertheless, further reduction of the hexahydroquinoline compound was still required. In other hand, Salunkhe et al. described the silica sulfuric acid application towards the synthesis of quinoline-4-carboxylic acids (35), with simple reagents and mild reaction conditions (Scheme 9).60 The catalyst could be removed by simple filtration and reused four times without loss of catalytic activity. This method has not been explored in the synthesis of quinolines bearing different functional groups at C-2, C-3 and C-4. As so, further investigation should be pursued given the environmental and monetary advantages of this synthetic route.

Scheme 9 Others. Rehan et al. reported the one pot sequential synthesis of 2,4-disubstituted quinolines from anilines and cinnamyl alcohols using Re2O7 as a Friedel-Crafts catalyst and KOtBu/DMSO as a catalyst for the oxidative cycloannulation. The reaction proceeded with moderate yields in acetonitrile and in long reaction times.61 Moreover, a MCR was used in the synthesis of polysubstituted quinoline-2-carboxylates (38) from anilines (11), ethyl glyoxylate (36) and styrene (37), with FeCl3 catalysis and TEMPO+BF4- as oxidant (Scheme 10).62 The reaction proceeded with moderate to good yields during long periods of time. Great excess of styrene and oxidant are huge setbacks to the scale-up of this synthesis.


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Scheme 10 Finally, two important works presented solid-supported acid catalysis in the Friedländer reaction. PEG-bound sulfonic acid63 and SiO2-HClO464 catalysts delivered excellent yields in short reaction times, providing easy separation and no loss of catalytic activity after several cycles. Nevertheless, further studies should be performed in order to improve the functional group flexibility of these methods. C) Biocatalytic synthesis Niewerth et al. described a remarkable synthesis of mixtures of 2-alkylquinolin-4(1H)-ones from biomass with recombinant Pseudomonas putida KT2440. Nevertheless, this study stands only as a starting point towards sustainable biocatalysed synthesis of quinolines, as the long reaction time, particularly low yield and the need of high performance liquid chromatography to isolate pure alkylquinolines invalidate its industrial application.65 D) Ultrasonication The use of ultrasounds towards the synthesis of heterocyclic compounds has recently been pursued for its mild and green conditions. However, sonication techniques still remained relatively unexplored for the synthesis of quinolines. Venkanna et al. published the synthesis of 2-chloroquinoline-3-carbaldehydes from acetanilide and a Vilsmeier-Haack reagent made from cyanuric chloride and N,N-dimethylformamide (TCTA/DMF).66 This reaction proceeded with excellent yields and short reaction times.


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Nevertheless, the use of non-recoverable organic solvents, the acute toxicity of TCTA and the low-biodegradability of its hydrolysis product pose major environmental concerns. An ultrasound-assisted four component MCR has been proposed for the synthesis of highly functionalised 1,4,6,8-tetrahydroquinolines.67 The reaction was performed in water, with K2CO3 catalysis, at room temperature and with short reaction times. Moreover, great yields were achieved for a limited variety of functional groups. Although this method provides a rapid, inexpensive, and green synthesis, a very restricted range of substituents was tested and a further reduction is still required to achieve the quinoline scaffold. Finally, two distinct methods described the ultrasound-assisted synthesis of quinolines in ILs. Heravi describes a Friedländer route in [Hbim][BF4] with excellent yields and great functional group flexibility.68 Furthermore, the reaction progressed at room temperature and the IL could be recycled without significant loss of activity. Sonication has also been applied towards the Pfitzinger reaction of isatin with ketones, already described above. This reaction presents similar advantages but allowed the synthesis of quinolones bearing different functional groups, namely 4-carboxylic acid derivatives.69 E) Photocatalysis Few methods have been described for the photocatalytic synthesis of quinolines, mainly due to the low yields and high quantity of side-products normally achieved. Two studies reported C-N bond formation through activation with a leaving group and UV (Scheme 11 – route 1) or white light (Scheme 11 – route 2) promoted cyclization and elimination.70,71 In the second, Jiang et al. described an iridium catalyst for the cyclization of acyl oximes in dry DMF and using white LED lights. Even though the reaction proceeded during 10 hours, low energy consumption could still be achieved due to LED technology (5 W lamps).


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Scheme 11 Mitamura and Ogawa have presented an outstanding synthesis of 2,4-diiodoquinolines (42) as great scaffolds for further cross-coupling reactions (Scheme 12).72 They performed the intramolecular cyclization of ortho-alkynylaryl isocyanides (41) with molecular iodine and UV radiation, with good yields and in considerably less time than most photocatalysed reactions. However, the use of chloroform as solvent is reprehensible and a topic for further investigation. This reaction is unique in presenting 100% atom economy. The authors also demonstrated the ability to selectively functionalise the quinolines formed, with nearly no side products.

Scheme 12 Finally, a photocatalytic study has been reported for the synthesis of 2-methylquinoline (44) from an ethanol solution of nitrobenzene (43) with suspended TiO2 nanoparticles (Scheme 13).73 Good yields have been attained under five hour’s reaction time. Nevertheless, the use of nitrobenzene does pose safety concerts. Moreover, a significant amount of by-products is reported and the variety of substitutions possible is very limited.


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Scheme 13 F) Ball milling High speed ball milling (HSBM) has become highly sought out due to the high energy generated in sphere collision. As so, some procedures have already been reported towards the synthesis of quinoline derivatives. First, Tan et al. presented the synthesis of 1,2,3,4-tetrahydroquinolines through a MCR catalysed by FeCl3 in solvent-free conditions under HSBM. Great yields were achieved in short reaction times. Besides, the reaction was performed at room temperature therefore reducing the energy consumption.74 Unfortunately no extension of this procedure has been reported towards the synthesis of quinolines. Nevertheless, an adaptation to the conventional Friedländer synthesis with PTSA has been reported with ball milling. The reaction proceeded at room temperature, in short reaction times and with high yield for a great variety of functional groups.75 As so, it proved the potential utility of ball milling as a non-thermal energy source for the synthesis of the quinoline scaffold. NON-ENERGY EFFICIENT GREEN REACTIONS Aqueous medium. Numerous methods have been published towards environmental friendly Friedländer reactions in water. Wang et al. described a fast and efficient synthesis of 2,3,4trisubstituted quinolines with a stoichiometric amount of hydrochloric acid.76 Still, the use of non-recoverable inorganic acids presents some ecological concerns.


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As so, different heterogeneous catalysts have been applied due to their recyclability: Zr(NO3)477 or Zr(DS)478 proceeded in great yields at short reaction times. Moreover, the presence of a surfactant, dodecyl sulfate (DS), appeared to increase the versatility of this method towards more polar functional groups. Besides, a mixture of water and a sulfonic acid combined IL allowed to obtain greater yields in overall shorter reaction times and lower temperatures. The task specific ionic liquid (TSIL) used lost no catalytic activity after several reaction cycles.79 Four MCR in water have described the synthesis of quinoline derivatives, with resource to cellulose supported Fe3O4 NPs,80 Montmorillonite-K10,81 ZnO NPs in a biphasic water/CTAB system82 (Scheme 14) or DABCO/TEAB.83 The first three catalysts mentioned presented great yields and were easily recovered and reused without significant loss of catalytic activity. Moreover, the DABCO/TEAB catalyst provided similar yields with a significant reduction of reaction time. A final remark must be made to the biphasic method, where the entire reaction media could be reused due to product extraction through liquid-liquid separation in ethyl acetate. As so, this method accomplished not only the green goals previously mentioned but also prevented the contamination of potable water.

Scheme 14


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Others. The use of efficient energy sources and/or aqueous reaction media must be a priority towards a greener synthesis. Nevertheless, other methods cannot be disregarded as they can reduce the environmental impact of catalysts and increase reaction yield or accessibility to different substitution patterns. Also, these methods have a particular interest as they present the most potential for further development under some of the techniques already mentioned. Several methods must be highlighted for the Friedländer synthesis of quinolones under conventional conditions, all regarding the use of heterogeneous and recyclable catalysts. Fe3O4@SiO2-imid-PMAn 84, Ni NPs85, sulfamic acid86 and nano-flake ZnO87 catalysts have all presented great yields in solvent-free conditions for a great variety of substituents. Moreover, the first three methods were performed in short reaction times (under 1 hour) and required only 5%10% mol of catalyst to reach full catalytic activity. Nickel nanoparticles present a distinguishing mark from other nanocatalysts as they were biofabricated from an aqueous leaf extract. Transition-metal catalysis has also been employed towards the oxidative Friedländer reaction of 2-aminobenzyl alcohols with enolisable ketones in the presence of oxygen and a hydrogen acceptor. Although similar methodologies have already been described in the sections above, high temperature synthesis in basic medium and with RuCl2(PPh3)3/1-dodecene,88 CuCl2/O2,89 palladium/O2,90 RuCl2(DMSO)4/O291 or Ag-Pd alloy supported on carbon92 catalysis is also reported. Also, a Ru-grafted hydrotalcite (HT) catalyst combining oxidative and acid catalytic properties was described, therefore eliminating the need for a non-reusable inorganic acid or base.93 No true advantage could be found from these methods due to the high cost of catalyst production, high variable yield and long reaction times, sometimes in toxic organic solvents. Moreover, pure oxygen atmosphere is usually required, posing significant safety concerns.


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Three very similar MCR procedures involving aniline, aldehydes and phenylacetylene, at temperatures between 70ºC and 120ºC have been disclosed. Syntheses catalysed by HClO4modified Montmorillonite,94 Fe(OTf)395 or Yb(Pfb)396 were performed with good yields and with excellent recyclability rates. Yet, a thorough synthesis of different substituents was only performed in Fe(OTf)3, revealing good yields. Remarkably this synthesis also had the shortest reaction times. Finally, Ir/TiO2 nanoclusters (NC) were used towards the already reported sequential transfer reduction-condensation-dehydrogenation reaction of nitroarenes with alcohols for the synthesis of 2,3-disubstituted quinolines.97 Good yields were achieved from simple reagents and in solvent-free conditions. Nevertheless, this procedure presents some limitations regarding the relation between C-2 and C-3 substituents which cannot be surpassed. Long reaction times and an inert atmosphere are still requirements.


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Table 1. Summary of green methods towards the synthesis of quinolines and calculation of diverse green metrics. Energy Supply

Solvent

Reaction

Yield (%)

Compound

AE (%)

E-FactorA

EMYB Ref.

400 W

6-12 min

50 - 89

2,4-dimethylquinoline-3-carboxylic acid

66.8

3.28

0.38

24

DPP

137ºC

12 min

13 - 98

1,4-bis(4-phenylquinolin-2-yl)benzene

87.0

0.23

4.35

25

SiO2 NPs

100ºC

5-15 min

80 - 93

3,3-dimethyl-9-phenyl-3,4-dihydroacridin-1(2H)one

89.3

0.12

8.33

26

SnCl2.2H2O

1050 W

3+2 min

55 - 80

1,2,3,4-tetrahydroacridine

53.5

1.48

0.68

27

-

250ºC

15 min

67 - 95

4-methyl-3-phenyl-6-(trifluoromethyl)quinolin2(1H)-one

43.3

0.65

1.54

33

PTSA

320 W

2 - 5 min

63 - 99

4-methylquinolin-2(1H)-one

54.6

0.26

3.85

34

PPA

400 W

20+20 min

35

4-hydroxyquinolin-2(1H)-one

-C

6.47

0.54

35

NaH

110ºC

3 min

90

methyl 2,4-dihydroxyquinoline-3-carboxylate

73.7

0.15

6.67

36

NaHSO4

360W

4-6 min

71,30%

2-methylquinolin-4(1H)-one

71.3

3.54

8.19

37

-

500 W

15 min

0 - 94

4-hydroxy-3-phenylquinolin-2(1H)-one

72.0

0.49

2.04

38

YCl3

180ºC

8 min

50 - 93

2,4-diphenylquinoline

93.4

0.11

9.09

28

In(OTf)3

720 W

8 min

81 - 90

methyl 2-(4-fluorophenyl)benzo[h]quinoline-4carboxylate

94.3

0.35

2.86

29

1. RuH2CO(PPh3)3/ Xantphos 2. TFA/CH3CHCHCN j k

130ºC

60 + 180 min

15 - 74

3-pentyl-2-phenylquinoline

96.5

1.8

0.56

30

-

100ºC

1-2:30 min

91 - 95

7-chloro-6-fluoro-2-phenylquinoline-4-carboxylic 88.8 acid

0.06

> 10

31

TiO2 nanopowder

150 W

1:10 min

68 - 85

2-hydroxy-4-phenylquinoline-3-carbonitrile

82.6

0.69

1.45

32

Oxidative Friedländer

T3P®-DMSO

60ºC

10 + 5 min

85 - 95

2-(quinolin-2-yl)phenol

31.8

> 10

4..83

39

MCR

-

110ºC

30 min

18 - 50

7,8-dimethyl-3-phenylquinoline

96.7

0.39

2.58

40

-

920 W

1:40 min

67 - 76

quinoline

69.7

1

1

41

Acetic acid

205-230ºC

5 min

25 - 75

6-methoxy-2-methylquinolin-4(1H)-one

74.7

9.84

0.1

44

NaOH

110ºC

10-15 min

82 - 93

quinoline-2,4-dicarboxylic acid

73.1

4.15

0.24

45

H2SO4

210ºC

10 min

41

quinoline

45.6

1.9

0.53

46

K5CoW12O40.3H2O (POM)

800 W

5-15 min

87 - 99

6-nitro-4-phenyl-2-(p-tolyl)quinoline

94.4

0.09

> 10

42

Pd(Ph3)2Cl2/CuI

120-150ºC

30 min

62 - 94

N,N-dimethyl-4-[2-(quinolin-2-yl)vinyl]aniline

47.9

> 10

0.09

43


ConradLimpach Solvent-free

MW MCR

Ionic liquids

Temperature/ Time (hours) Power

HCl Friedländer

Ethanol

Catalyst

DoebnerMiller ConradLimpach Pfitzinger

Others MCR


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Solvent-free

Friedländer

SiO2/I2

60ºC

1,5-15 h

50-97

ethyl 6-chloro-2-methyl-4-phenylquinoline-3carboxylate

90.0

0.9

3.05

47

T3P®

60ºC

30-60 min

85-96

7-chloro-9-phenyl-1,2,3,4-tetrahydroacridine

45.3

1.45

2.67

48

89.0

0.1

> 10

51

-

50ºC

6-12 h

86-93

2,7,7-trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8hexahydroquinoline-3-carbonitrile

Zn(OTf)2

80-90ºC

2-2:30 h

90-98


94.0

0.21

4.76

49

-

100ºC

3-6 h

90-98

9-methyl-2,3-dihydro-(1H)cyclopenta[b]quinoline

83.6

0.05

> 10

50

Zn/HCO2NH4

50ºC+12MPa

60 min

74-79

3,4-dihydroquinolin-2(1H)-one

45.8

5.99

2.87

52

Amberlyst – 15

78ºC

2-3:30 h

69-93

89.0

> 10

6.67

53

NaAuCl4.2H2O

RT to 60ºC

42 h

50-93

90.0

> 10

7.42

54

ZrO2/Fe3O4-MNPs

70ºC

30-65 min

86-92

90.0

> 10

8.78

55

Alkoxyamine linker

78ºC

24+24 h

40-78

62.1

> 10

0.02

56

SnCl2/ZnCl2

70ºC

3:00 h

80-98

3-ethyl-2-propylquinoline

33.7

> 10

0.1

57

MgO-NPs

78ºC

17 - 43 min

87-92

2-amino-7,7-dimethyl-5-oxo-1,4-diphenyl1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile

95.4

> 10

9.64

59

Silica Sulfuric Acid

78ºC

3-3:30 h

68-84

2-phenylquinoline-4-carboxylic acid

86.8

> 10

> 10

60

Lactic acid

80ºC

2:30 h

75-95

1-(2,4-dimethylquinolin-3-yl)ethan-1-one

84.7

6.46

> 10

58

PEG-bound sulfonic acid

40ºC

40 – 90 min

90-96

ethyl 2,4-dimethylquinoline-3-carboxylate

86.4

> 10

0.02

63

HClO4-SiO2

60ºC

2-3 h

90-96

1-(2,4-dimethylquinolin-3-yl)ethan-1-one

84.7

> 10

0.04

64

MCR

FeCl3 / TEMPO+BF4-

60ºC

18 h

20-95

ethyl 6-methyl-4-phenylquinoline-2carboxylate

52.4

> 10

0.02

62

Others

ReO7 /KOtBu, DMSO

RT

(8-12) + 4 h

51-56

6-methyl-2,4-diphenylquinoline

68.8

> 10

0.02

61

Friedländer

-

RT

10 - 35 min

65-93

6-chloro-2,3-dimethyl-4-phenylquinoline

88.1

1.4

2.51

68

MCR

K2CO3

RT

12 - 15 min

2-amino-4-(4-methoxyphenyl)-7,7-dimethyl5-oxo-1,4,5,6,7,8-hexahydroquinoline-3carbonitrile

77.1

0.16

2.85

67

Pfitzinger

Ionic liquid

RT

2h

62-96

2-phenylquinoline-4-carboxylic acid

93.3

0

-

69

Other

-

RT

35 - 90 min

85-90

2-chloroquinoline-3-carbaldehyde

48.8

> 10

0.03

66

Triethylamine

RT

10 - 120 min

28-87

benzo[4,5]thieno[2,3-c]quinolin-6(5H)-one

64.6

> 10

0

70

fac-[Ir(ppy)3]

RT

10 h

46-88

ethyl 2-methylquinoline-3-carboxylate

53.1

> 10

0.07

71

RT

4h

0-86

2,4-diiodo-3-phenylquinoline

100

> 10

0.04

72

MCR Ionic liquids Others Supercritical solvents (CO2)


Friedländer Mild Temperatures

Ethanol Oxidative Friedländer MCR

Lactic acid

Friedländer

Friedländer Organic solvents

Ionic liquid

Sonication

Aqueous medium

DCM

Photocatalysis

Organic solvents

Other

I2

ethyl 2-methyl-4-phenylquinoline-3carboxylate ethyl 2-methyl-4-phenylquinoline-3carboxylate ethyl 6-chloro-2-methyl-4-phenylquinoline-3carboxylate ethyl 2-methyl-4-phenylquinoline-3carboxylate


23


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EtOH Ball Milling

Other

TiO2 nanocatalyst

30ºC

5h

20-80

Friedländer

PTSA

RT

30 - 150 min

38-96

MCR

FeCl3

RT

30 - 90 + 90 min

70-91

HCl

60ºC-90ºC

30 - 300 min

85-96

Zr(NO3)4

100ºC

3 - 40 h

84-99

Zr(DS)4

100ºC

0,5 - 6 h

63-98

Ionic liquid - TSIL

70ª - 90º C

1-8h

85-98

Solvent free

Friedländer

Aqueous medium

Organic solvents


MCR

Solvent free Friedländer

Ethanol

Other

1-(2-methyl-4-phenylquinolin-3-yl)ethan-1-one 6-methyl-2-(3-nitrophenyl)-4-phenyl-1,2,3,4tetrahydroquinoline ethyl 4-(4-fluorophenyl)-2-methylquinoline-3carboxylate 7-chloro-3,3-dimethyl-9-phenyl-3,4dihydroacridin-1(2H)-one ethyl 6-chloro-2-methyl-4-phenylquinoline-3carboxylate ethyl 2-methyl-4-phenylquinoline-3-carboxylate 1,3,8,8-tetramethyl-5-phenyl-5,8,9,10tetrahydropyrimido[4,5-b]quinoline2,4,6(1H,3H,7H)-trione ethyl 2-(3,4-difluorophenyl)-6,7dimethoxyquinoline-3-carboxylate 5-(4-chlorophenyl)-1,3-dimethyl-5,12dihydrobenzo[g]pyrimido[4,5-b]quinoline2,4,6,11(1H,3H)-tetraone 2-amino-7,7-dimethyl-5-oxo-1,4-diphenyl1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile

84.7

> 10

0.86

73

87.9

0.32

3.12

75

95.0

0.58

1.73

74

89.6

0.17

> 10

76

90.3

0.13

7.7

77

90.0

0.23

4.32

78

89.0

0.02

> 10

79

91.0

0.14

7.36

80

76.9

0.43

2.32

81

97.8

0.05

> 10

82

95.4

0.18

5.5

83

Fe3O4 - MNPs supported on cellulose

100ºC

2h

86-96

montmorillonite K-10

90ºC

5 - 10 h

62-89

ZnO nanocatalyst

80ºC

4h

89-95

DABCO-TEAB

100ºC

15 - 30 min

82-92

RuCl2(PPh3)3/KOH/ 1-dodecene

80ºC

20 h

43-90

2-phenylquinoline

43.7

> 10

0.05

88

CuCl2 / O2 / KOH

100ºC

5h

44-82

2-phenylquinoline

68.1

> 10

0.03

89

Pd(OAc)2 / PEG-2000

100ºC

20 h

35-94

2-phenylquinoline

68.1

> 10

0.06

90

80ºC

24 h

30-96

2-phenylquinoline

68.5

7.6

0.18

91

125ºC

21+21 h

15-74

3-benzyl-2-phenylquinoline

47.7

> 10

0.14

92

Ru / HT

100ºC

20 h

35-84

2-phenylquinoline

84.4

> 10

0.04

93

HClO4Montmorillonite

70ºC

4h

41-81

2-(4-chlorophenyl)-4-phenylquinoline

94.0

7.14

0.14

94

Fe(OTf)3

100ºC

3h

66-88

4-phenyl-2-(p-tolyl)quinoline

93.7

0.32

3.08

95

MCR

Non-energy efficient

2-methylquinoline

Page 24 of 49

RuCl2(DMSO)4/ KOH / PhCOPh Ag-Pd nanoparticles (1:2)

Yb(Pfb)3

80º-120º C

12 h

63-92


93.4

0.24

4.24

96

Fe3O4 @ SiO3-imidPMAn

70ºC

30 - 70 min

90-96

ethyl 2-methyl-4-phenyl quinoline-3-carboxylate

89.0

0.06

> 10

84

Ni-NPs

75ºC

50 - 76 min

87-96


89.0

0.09

> 10

85

HNH2SO3H

70ºC

30 - 90 min

82-95


89.0

0.12

8.54

86

Nano-Flake ZnO

100ºC

2 - 12 h

60-98

ethyl 2,4-dimethylquinoline-3-carboxylate

86.4

0.03

> 10

87

Ir/TiO2 - NCs

120ºC

7 - 28 h

60-92

2-ethyl-3-methylquinoline

70.4

> 10

8.54

97

All metrics were calculated using only reaction data. In order to achieve similar conditions, extraction and purification procedures were not accounted for. Moreover, results in E-factor and EMY above 10 were considered as such to reduce its impact on further analysis. A result of this magnitude already represents a ACS Paragon Plus Environment

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significantly environmentally good/bad method. ARecyclable solvents and/or catalysts (>95%) were not considered in the calculations. BAll reagents were considered as toxic to discard product variability as a factor. CCatalyst has no defined molecular mass.


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DISCUSSION As shown, an extensive collection of green methods towards the synthesis of the quinoline scaffold has been developed over the years. Thus, a mere description of the reaction conditions as the one given so far cannot readily show which methods are best suitable to a given application. The resource to green metrics takes great importance as a prompt way to compare the environmental impact of the referred synthesis. Table 1 summarizes the studies mentioned, therefore allowing for a more intuitive search of green reactions towards the synthesis of quinolines. Moreover, three distinct metric systems were calculated and presented as they provide different perspectives in the green context. Atom Economy (AE) allows us to consider the mass of reagents incorporated in the final product, taking in consideration only the stoichiometry of the reaction itself and possible deracemization processes required.98 AE (%)=

M.W. of desired product ×100 ∑ M.W. reagents

On the other hand, the E-factor considers the waste generated in a certain chemical reaction, including yield, catalysts and even the solvents used.98 E-factor=

Mass of waste Mass of product

A more environmental accurately metric can also be achieved with Effective Mass Yield (EMY) as it allows for a weighted measure of only the toxic waste produced, highlighting the advantages of, for example, the use of benign solvents or catalysts.98 EMY=

Mass of product Mass of non-benign waste

The unique opportunity provided by joining a wide range of synthetic approaches to a scaffold on a common database, with three distinct metric systems, allows us to present a brief statistical analysis through the use 3D scatter plots. Additional confirmation was obtained with the help of


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a clustergram. The graphics were achieved after data normalization and using MATLAB 7.14.0.739 (The MathWorks Inc., Massachusetts, USA). It can be inferred from Figure 3 that both the Friedländer reaction and the diverse MCR’s studied show better atom economy indexes than other methods, therefore proving optimal conditions for natural resource conservation. Unfortunately, this advantage does not limit the amount of waste produced, as no correlation was verified between the different reactions and the other green metrics. Additional clustergram confirmation is presented in Figure 6.

Figure 3. 3D representation of the green metrics calculated for each article. Red – Friedländer; yellow – oxidative Friedländer, green – Conrad-Limpach, blue – Pfitzinger, cyan – MCR, magenta – Doebner-Miller, black – Others. Moreover, Figure 4 shows a correlation between two of the green metrics, E-factor and EMY, and the use of different solvents. As expected, better green indexes are verified with the use of water or solvent-free conditions, and ILs displayed similar range of results as they present great recyclability and therefore were generally not accounted for waste calculation. Despite having high E-factor values, reactions in ethanol also show low toxic waste production due to their


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Page 28 of 49

biocompatibility. As so, they represent a more versatile and attractive alternative to organic solvents in industrial applications, reducing the costs with solvent waste treatment. Additional separation by atom economy index could also be verified in the clustergram shown in Figure 6.

Figure 4 - 3D representation of the green metrics calculated for each article. Red – solvent-free, yellow – ethanol, green – IL, blue – aqueous system, magenta – SC, cyan – organic solvent, black – other solvents. Unfortunately, in Figure 5 no simple correlation was verified between energy systems and either of the three green metrics. Still, a tendency towards low E-factors with the use of microwave irradiation (MWI) occurs due to its receptivity towards solvent-free methodologies.


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Figure 5 – 3D representation of the green metrics calculated for each article. Red – MWI, yellow – mild temperatures, green – sonication, blue – photochemical, cyan – ball milling, black – nonenergy efficient.

Figure 6 - Clustergram of the methods towards the synthesis of quinolines and its green factors, labelled with: 1 - the synthetic route applied; 2 – the solvent used; 3 – the energy supply system.


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CONCLUSIONS The wide range of possible industrial and pharmacological applications for the quinoline scaffold calls for a constant search in more environment-friendly methods towards its synthesis. In this work, we have compiled and organized most green methods developed, providing an intuitive and simple tool for the common researcher to plan further investigation in this subject. A critical review of the referred methods is also given, presenting disadvantages that may at first be unclear to the reader. Furthermore, the unique assembly of data on a table format presenting several green metrics and posterior statistical analysis allowed us to withdraw some fascinating conclusions. It was possible to determine that the use of Friedländer or MCR reactions, to improve atom economy, and the use of solvent-free conditions, water or ionic liquids, to reduce waste production, is preferable in the design of new methodologies. Moreover, we’ve found that in specific cases the use of microwave irradiation can be most compatible with the previous reaction conditions and therefore provide an energy efficient method for further exploitation. Finally, we would like to highlight that the use of more recent high pressure, continuous flow and biocatalysis techniques with industrial scale relevance has yet to be successfully reported and should be considered as essential in future research. Corresponding Author *E-mail: [email protected] ACKNOWLEDGMENT Thanks are due to the University of Aveiro and Fundação para a Ciência e a Tecnologia (FCT) FCT/MEC for the financial support of the QOPNA research Unit (FCT UID/QUI/00062/2013)


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through national founds and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement. ABBREVIATIONS CTAB - cetyl trimethylammonium bromide; DABCO - 1,4-diazabicyclo [2,2,2] octane; DCM – dichloromethane; DMSO – dimethylsulfoxide; IUPAC - International Union of Pure and Applied Chemistry; LED - light emitting diode; OLED - organic light emitting diode; PEG - polyethylene glycol; PMA - poly(methylacrylate); SC – supercritical; T3P® - Propane Phosphonic Acid Anhydride; TCTA - tris(4-carbazoyl-9-ylphenyl)amine; TEAB - tetraethylammonium bromide; TEMPO - 2,2,6,6-tetramethylpiperidinyloxy. REFERENCES (1)

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which Are the Best? Green Chem. 2002, 4 (6), 521–527.


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For Table of Contents Use Only Synthesis of Quinolines: A Green Perspective Vasco F. Batista, Diana C. G. A. Pinto,* Artur M. S. Silva

Synopsis Important green metrics were analysed and will allow the choice of the best sustainable approaches towards quinoline synthesis


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Vasco F. Batista is a M.Sc. student at Universidade de Aveiro (UA), institution in which he completed his B.Sc. in Chemistry. He is also currently undergoing a short-term internship at the Manchester Institute of Biotechnology (MIB). He participated in the International Chemistry Olympiads (ICHO) and in the Iberoamerican Chemistry Olympiads (OIAQ) in 2011, obtaining a bronze medal in the latter. He was also awarded a Merit Scholarship by his host university in the years 2011, 2012 and 2013. His main interests are in the green chemistry field, specifically related to the synthesis of pharmaceutically relevant molecules through the use of microwave irradiation or enzyme engineering.

Diana C. G. A. Pinto studied chemistry at the University of Aveiro (Portugal) where she graduated in analytical chemistry in 1991. In 1996 she received her PhD in chemistry at Aveiro University. She then joined the Department of Chemistry at Aveiro University where she is currently Assistant Professor of Organic Chemistry. Diana is an expert in organic synthesis, includes the development of new strategies towards the synthesis of nitrogen and oxygen heterocyclic compounds that can be used as new drugs. Over the years, her research has also been focused on the application of environmental friendly methodologies in organic synthesis, with prominence on the application of microwave irradiation. Besides her strong interest in organic synthesis, Diana is also developing an active research in isolation and characterization of natural products, focusing on medicinal plants. Currently, she is the author and co-author of 91 SCI papers and 7 book chapters. She supervised more than 20 students’ between PhD and MSc and she also participated in financed Portuguese and European projects.


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Artur M. S. Silva is currently full professor at the Chemistry Department, University of Aveiro. He is also the vice-president of the Portuguese Chemical Society. He obtained both the BSc in Chemistry-Physics (1987) and the PhD in Organic Chemistry (1993) degrees at the University of Aveiro. He joined the Department of Chemistry of the same University in 1987 as Assistant and was appointed to Auxiliary Professor in 1996, Associate Professor in 1999 and Full Professor in 2001. He published more than 490 SCI papers, 24 book chapters and delivery more than 45 lectures in scientific meetings. His publications have been cited by more than 7150 times and his Hirsch-index is 39. He supervised 21 PhD students and 31 MSc students; he has also participated in 16 financed Portuguese and European projects and in 8 bilateral financed projects with European Research Groups. His research interests range over the chemistry of polyphenolic and nitrogen heterocyclic compounds, with special emphasis on the development of new sustainable synthetic routes, and also on the organocatalytic and metal-catalysed transformations. The second passion of his research is centred in the isolation and structural characterization of natural products from diverse terrestrial and marine sources. But all these scientific activities it is supported in his strong knowledge on NMR spectroscopy. The third axis of their research are focused on the synthesis of biologically active oxygen and nitrogen heterocyclic compounds, as well as on the evaluation of their antioxidant, anti-inflammatory, antitumor and antimicrobial activity in collaborations with other Portuguese and International research groups.


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Synthesis of Quinolines: A Green Perspective - ACS Publications

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