Glycerol and Q-Tubes: Green Catalyst and Technique for Synthesis of Polyfunctionally Substituted Heteroaromatics and Anilines

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Article Glycerol and Q-Tubes: Green Catalyst and Technique for Synthesis of Polyfunctionally Substituted Heteroaromatics and Anilines

Douaa Salman AlMarzouq 1,* and Noha M. Hilmy Elnagdi 2,* 1 Department of Environmental Health, College of Health Sciences, the Public Authority of Applied Education and Training, P.O. Box 23167, Safat 13092, Kuwait 2 Department of Organic Chemistry, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, P.O. Box 12518, Cairo 11511, Egypt * Correspondence: [email protected] (D.S.A.); [email protected] (N.M.H.E.); Tel.: +965-9793-2529 (D.S.A.); +20-110-557-3654 (N.M.H.E.) Received: 2 April 2019; Accepted: 7 May 2019; Published: 10 May 2019

Abstract: The role of glycerol as a green bio-based solvent, reactant, and/or a catalyst in the synthesis of novel heterocycles, under pressure, is studied. Synthesis of novel quinolines in good yields using a new modiﬁed Skraup synthesis, utilizing glycerol and pressure Q-tubes, is demonstrated. Novel aniline trimers are prepared using glycerol, and substituted anilines under pressure, in acidic medium and water. Glycerol was employed as a catalyst and a green solvent in the synthesis of novel pyridazines 13a–c. The mechanisms of the reactions and the catalytic eﬀect of glycerol in protic and aprotic media are fully discussed. The structures of the synthesized compounds were determined via X-ray crystallography and spectroscopic methods.

Keywords: glycerol; green chemistry; modiﬁed Skraup’s quinoline synthesis; reactions under pressure; Q-tubes; polyaniline

1. Introduction Glycerol was first isolated by the Swedish chemist: Carl W. Scheele, in 1779, upon treatment of olive oil with lead oxide [1,2]. Glycerol or propane-1,2,3-triol 1 is now produced in large quantities as a byproduct in many industries [3–5]. The large-scale production of biodiesel from fats, where glycerol is a waste product, has made glycerol a highly economic solvent and reactant [6–12]. This has attracted many researchers in the last two decades to find routes for converting this surplus into value added products [13–24]. Some of glycerol’s utilities in chemical industries are summarized in Scheme1. Since glycerol is highly hygroscopic and stable at high temperatures (B.P. = 290 ◦C), in addition to being environmentally friendly, nontoxic, nonvolatile, inflammable, non-corrosive, cheap, biodegradable, and recyclable, it could be considered a green medium and solvent in organic synthesis [25–27]. According to Arrhenius, the reaction rate doubles for every 10 ◦C rise in temperature [28]. Thus, glycerol would simply decrease the time of many reactions that take place in other low boiling-point solvents. Recently, Hamid et al. discussed the catalytic effect of glycerol by H-bond formation, which facilitates addition and condensation processes [29]. Glycerol has not yet been fully explored in the field of organic synthesis and catalysis. However, some studies have suggested that glycerol is a medium in “catalyst-free” reactions [30–32]. We think that these studies have neglected the possibility that glycerol itself acts as a catalyst in such reactions. One of the oldest utilities of glycerol in organic chemistry is the synthesis of quinolines in poor yields, known as the “Skraup synthesis of quinolines” [33,34]. Skraup’s synthesis of quinolines has many limitations other than the low yield, including the multi-step addition of the reactants, in which

Molecules 2019, 24, 1806; doi:10.3390/molecules24091806 www.mdpi.com/journal/molecules Molecules 2019, 24, 1806 2 of 14

glycerol must ﬁrst react with H2SO4 to yield the hazardous acrolein (propenal), which is followed by the addition of the aromatic amine to form hydroquinoline that is converted to the quinoline by adding Moleculesan oxidizing 2019, 24 agent FOR PEER as the REVIEW ﬁnalstep (cf. Scheme2). 2

Scheme 1. Some industrial uses of glycerol. Scheme 1. Some industrial uses of glycerol. Molecules 2019, 24 FOR PEER REVIEW 3 Since glycerol is highly hygroscopic and stable at high temperatures (B.P. = 290 °C), in addition to being environmentally friendly, nontoxic, nonvolatile, inflammable, non-corrosive, cheap, biodegradable, and recyclable, it could be considered a green medium and solvent in organic synthesis [25–27]. According to Arrhenius, the reaction rate doubles for every 10 °C rise in temperature [28]. Thus, glycerol would simply decrease the time of many reactions that take place in other low boiling-point solvents. Recently, Hamid et al. discussed the catalytic effect of glycerol by H-bond formation, which facilitates addition and condensation processes [29]. Glycerol has not yet been fully explored in the field of organic synthesis and catalysis. However, some studies have suggested that glycerol is a medium in “catalyst-free” reactions [30–32]. We think that these studies have neglected the possibility that glycerol itself acts as a catalyst in such reactions. One of the oldest utilities of glycerol in organic chemistry is the synthesis of quinolines in poor yields, known as the “Skraup synthesis of quinolines” [33,34]. Skraup’s synthesis of quinolines has many limitations other than the low yield, including the multi-step addition of the reactants, in which glycerol must first react with H2SO4 to yield the hazardous acrolein (propenal), which is followed by the addition of the aromatic amine to form hydroquinoline that is converted to the quinoline by adding an oxidizing agent as the final step (cf. Scheme 2). Scheme 2. Reaction mechanism of the Skraup quinoline synthesis. Scheme 2. Reaction mechanism of the Skraup quinoline synthesis. Other limitations include the use of highly concentrated glycerol that contains less than one-half percentOther of waterlimitations known include as “dynamite the use glycerin”of highly toconcentr ensureated good glycerol yields [ 35that]. Precautionscontains less from than explosion one-half percentand physical of water hazards known control as have “dynamite to be employed glycerin” since to theensure reaction good is highlyyieldsvigorous [35]. Precautions due to the usefrom of explosion and physical hazards control have to be employed since the reaction is highly vigorous due nitrobenzene as an oxidizing agent and as a solvent. Prolonged heating in concentrated H2SO4, and the to the use of nitrobenzene as an oxidizing agent and as a solvent. Prolonged heating in concentrated H2SO4, and the formation of a thick tar, from which quinoline is difficult to extract are also among the problems of the Skraup synthesis. These limitations have urged researchers to attempt to modify the synthetic route, to increase the yield of the quinoline synthesis reactions, and to make it “greener.” The new modified synthesis of quinolines or “green recipes” [36] involve using green solvents or even solvent-less reactions, one-pot synthesis, new green catalysts alongside with new technologies such as microwave energy, ultrasonication, and grinding [37–49] There is now a boom in the use of high pressure in science [50], and reactions under high pressure and/or temperature proved to behave in a different manner than those under normal thermal conditions [51,52]. The newly invented borosilicate tubes known as Q-tubes have allowed the performance of difficult or otherwise impossible chemical reactions in chemical laboratories [53– 56]. Shifts in transition state along a reaction coordinate, a switch of the rate-determining step, and the possible transformation of a transition state into a stable minimum, are among the possible phenomena that can occur for reactions under pressure, especially in fluids [57]. A supercritical solvent is a solvent that is subjected to a temperature and pressure higher than those of its critical point. However, when both the temperature and/or the pressure are lower than those of the critical point, and the temperature is higher than that of the boiling point, with a pressure higher than 1 bar, a subcritical solvent is obtained. A subcritical solvent can be defined as a hot compressed solvent and, according to Galy et al., glycerol produces different products in subcritical and supercritical solvents [58]. In this study, we combined glycerol and water as green, efficient solvents, in addition to the pressure in Q-tubes, to modify the synthesis of quinolines and prepare new aniline trimers and pyridazines.

Molecules 2019, 24, 1806 3 of 14 formation of a thick tar, from which quinoline is difficult to extract are also among the problems of the Skraup synthesis. These limitations have urged researchers to attempt to modify the synthetic route, to increase the yield of the quinoline synthesis reactions, and to make it “greener.” The new modified synthesis of quinolines or “green recipes” [36] involve using green solvents or even solvent-less reactions, one-pot synthesis, new green catalysts alongside with new technologies such as microwave energy, ultrasonication, and grinding [37–49]. There is now a boom in the use of high pressure in science [50], and reactions under high pressure and/or temperature proved to behave in a different manner than those under normal thermal conditions [51,52]. The newly invented borosilicate tubes known as Q-tubes have allowed the performance of difficult or otherwise impossible chemical reactions in chemical laboratories [53–56]. Shifts in transition state along a reaction coordinate, a switch of the rate-determining step, and the possible transformation of a transition state into a stable minimum, are among the possible phenomena that can occur for reactions under pressure, especially in fluids [57]. A supercritical solvent is a solvent that is subjected to a temperature and pressure higher than those of its critical point. However, when both the temperature and/or the pressure are lower than those of the critical point, and the temperature is higher than that of the boiling point, with a pressure higher than 1 bar, a subcritical solvent is obtained. A subcritical solvent can be defined as a hot compressed solvent and, according to Galy et al., glycerol produces different products in subcritical and supercritical solvents [58]. In this study, we combined glycerol and water as green, efficient solvents, in addition to the pressure in Q-tubes, to modify the synthesis of quinolines and prepare new aniline trimers and pyridazines.

2. Results and Discussion We initially started our work with the synthesis of quinolines. Quinolines are extremely important in the pharmaceutical industry, especially in the treatment of malaria and cancer [59–61]. Fluoroquinolines are used in many pharmaceutical compounds, especially in fluoroquinolone antibiotics, such as ciprofloxacin (Cipro), gemifloxacin (Factive), levofloxacin (Levaquin), moxifloxacin (Avelox), norfloxacin (Noroxin), and ofloxacin (Floxin) [62,63]. Selivanova et al. found that reacting polyfluoro-2-naphthylamines with glycerol in H2SO4 or CF3SO3H at 150–160 ◦C gives, surprisingly, the respective polyfluorobenzo[f]quinolones, rather than the expected cyclization at the unsubstituted ortho-position [39]. We thought of investigating this phenomenon as well as modifying the Skraup quinoline synthesis using pressure Q-tubes, and studying the effect of glycerol in subcritical and supercritical solvents. Unlike the results reported by Selivanova et al., the reaction of 1 and 3a–b in the presence of conc. H2SO4, under pressure in a Q-tube at 200 ◦C proceeded to yield quinolines 6a and 6b, in 58% and 60% yield, respectively. To our knowledge, quinoline 6b has not been previously isolated (cf. Scheme3). Recently, Saggadi and co-workers synthesized 5-substituted, 6-substituted, 7-subsituted, and 8-substituted quinolines using microwave conditions, aniline derivatives, and glycerol in the presence of sulfuric acid and water. The desired quinolines were obtained in 10%–66% yields [64]. Surprisingly, in our hands, the reaction of aromatic amines, glycerol, sulfuric acid, and water in pressurized conditions afforded a compound with an m/z value of 359.23, which was, after other spectroscopic 1 investigations, assigned to 4,40,4”-(propane-1,2,3-triyl)tris(2-methylaniline) 7. The H NMR spectrum of compound 7 shows a singlet at δ = 2.00 ppm for 9H that is assigned to 3-CH3 protons, a multiplet at δ = 3.34 ppm for 5H of 2 methylene and 1 methine protons, and another singlet at δ = 5.01 ppm for 6H assigned for the 3 NH2 protons as well as a multiplet at δ = 7.13 for aromatic 6 protons. The 13 C-NMR spectrum of compound 7 shows a signal at δ = 146.53 assigned for 3C-NH2 at δ = 76.24 for 2CH2 and at δ = 16.95 for 3CH3. Conversely, when the unsubstituted aniline 3a was reacted under the same conditions, with glycerol and water under pressure (subcritical water), the aniline trimer 8 was the only product obtained. The structure of compound 8 was also confirmed via spectroscopic analysis. The mass spectrum of the reaction product 8 showed a molecular ion peak: m/z = 365.173 (100%). The 1H NMR spectrum revealed a singlet at δ = 2.4 ppm, integrated for 6H, which was assigned to the Molecules 2019, 24, 1806 4 of 14

3NH2 protons. Two doublets at δ = 3.27 ppm and 3.29 ppm for two aliphatic CH2 groups and multiplet atMoleculesδ = 3.35 2019 ppm, 24 FOR were PEER assigned REVIEW for the methine CH proton and another multiplet at 6.94 ppm were4 assigned for the aromatic protons. The 13C-NMR spectral results were in agreement with the proposed the expected cyclization at the unsubstituted ortho-position [39]. We thought of investigating this structure, which showed a signal at δ = 63.09 ppm, assigned to the 2 O-CH2 carbons, as well as another signalphenomenon at δ = 72.49 as well ppm, as assigned modifying to thethe O-CHSkraup carbon. quinoline It is worthsynthesis mentioning using pressure that trials Q-tubes, to use 3fand as thestudying starting the aniline effect of produced glycerol ain compound subcritical with and su anpercriticalm/z value solvents. of 410.5, forUnlike which the we results could reported not assign by anySelivanova reasonable, et al., suggested the reaction structure. of 1 and Table 3a–b1 summarizesin the presence our of results conc. andH2SO reaction4, under conditions pressure in of a the Q- reactionstube at 200 of °C glycerol proceeded with aromaticto yield quinolines amines under 6a and pressure. 6b, in 58% and 60% yield, respectively. To our knowledge, quinoline 6b has not been previously isolated (cf. Scheme 3).

Scheme 3. Reaction of aromatic amines, glycerol, and sulfuric acid in the presence/absence of water, Scheme 3. Reaction of aromatic amines, glycerol, and sulfuric acid in the presence/absence of water, under a high pressure, and high temperatures in the Q-tubes. under a high pressure, and high temperatures in the Q-tubes.

TableRecently, 1. Variation Saggadi ofand the co-workers nature of aniline synthesized products 5-su dependingbstituted, on 6-substitute the reactiond, conditions 7-subsituted, in the and 8- substitutedpresence quinolines and absence using of H2 O,microwave starting from conditions, glycerol 1 anilineunder a derivatives, high pressure, and and glycerol high temperatures in the presence in of sulfuricthe Q-tubes. acid and water. The desired quinolines were obtained in 10%–66% yields [64]. Surprisingly, in our hands, the reaction of aromatic amines, glycerol, sulfuric acid, and water in Reaction Conditions pressurizedEntry R conditionsR affordedR a compound with an m/z value of 359.23, whichMP. was, ( C) afterm other/z 1 2 3 Time Temp Product Yield% ◦ spectroscopic investigations, assignedMedium to 4,4′,4′′-(propane-1,2,3-triyl)tris(2-methylaniline) 7. The 1H (min.) (◦C) NMR spectrum of compound 7 shows a singlet at δ = 2.00 ppm for 9H that is assigned to 3-CH3 3a protons, a multipletH H at δ = 3.34 H ppm for glycerol 5H of 2 methylene 60 and 200 1 methine 6a protons, 58 and BP another= 238 singlet 3a H H H glycerol + H2O 15 160 8 73 240 365.17 at δ3b = 5.01 ppmF for F6H assigned H for the glycerol 3 NH2 protons 60 as well 200 as a multiplet 6b 60at δ = 7.13 243 for aromatic165.03 6 13 protons3c . TheCH 3 C-NMRI spectrum H glycerolof compound+ H2O 7 shows 15 a signal 160 at δ 7 = 146.53 75 assigned 180 for 3C-NH359.232 at δ = 3d76.24 forCH 32CH2Br and at H δ = 16.95 glycerol for +3CHH2O3. Conversely, 20 160 when the 7 unsu 70bstituted 180aniline 3a359.23 was reacted3e underCH3 the Clsame conditions, H glycerol with+ glycerolH2O and 20 water 160 under 7 pressure 70 (subcritical 180 water),359.23 the not aniline3f trimerH 8 was H the only Cl product glycerol obtained.+ H O The 30 structure 160 of compound 8- was also confirmed 410 via 2 concluded spectroscopic analysis. The mass spectrum of the reaction product 8 showed a molecular ion peak: m/z = 365.173 (100%). The 1H NMR spectrum revealed a singlet at δ = 2.4 ppm, integrated for 6H, While acrolein is a minor product of the dehydration of glycerol under neutral hydrothermal which was assigned to the 3NH2 protons. Two doublets at δ = 3.27 ppm and 3.29 ppm for two aliphatic conditions, it becomes the main product when an acid catalyst is added, but at temperatures above CH2 groups and multiplet at δ = 3.35 ppm were assigned for the methine CH proton and another multiplet at 6.94 ppm were assigned for the aromatic protons. The 13C-NMR spectral results were in agreement with the proposed structure, which showed a signal at δ = 63.09 ppm, assigned to the 2 O- CH2 carbons, as well as another signal at δ = 72.49 ppm, assigned to the O-CH carbon. It is worth mentioning that trials to use 3f as the starting aniline produced a compound with an m/z value of

Molecules 2019, 24 FOR PEER REVIEW 5

410.5, for which we could not assign any reasonable, suggested structure. Table 1 summarizes our results and reaction conditions of the reactions of glycerol with aromatic amines under pressure.

Table 1. Variation of the nature of aniline products depending on the reaction conditions in the

presence and absence of H2O, starting from glycerol 1 under a high pressure, and high temperatures in the Q-tubes.

Reaction Conditions Yield Entry R1 R2 R3 Time Product MP. (°C) m/z Medium Temp (°C) % (min.) 3a H H H glycerol 60 200 6a 58 BP = 238 3a H H H glycerol + H2O 15 160 8 73 240 365.17 3b F F H glycerol 60 200 6b 60 243 165.03 3c CH3 I H glycerol + H2O 15 160 7 75 180 359.23 3d CH3 Br H glycerol + H2O 20 160 7 70 180 359.23 3e CH3 Cl H glycerol + H2O 20 160 7 70 180 359.23 not 3f H H Cl glycerol + H2O 30 160 - 410 concluded Molecules 2019, 24, 1806 5 of 14 While acrolein is a minor product of the dehydration of glycerol under neutral hydrothermal conditions, it becomes the main product when an acid catalyst is added, but at temperatures above 340 ◦°CC using conventional heating [[58].58]. Under Under pressure, pressure, we could achieve the same results but at much lowerlower temperatures.temperatures. Thus,Thus, using using Q-tubes Q-tubes and and heating heating at onlyat only 200 200◦C for°C 1for h, 1 we hour, could we prepare could quinolinesprepare quinolines in high yields. in high Recently, yields. Recently, the catalytic the rolecatalytic of glycerol role of via glycerol H-bond via was H-bond published was bypublished Hamid andby Hamid coworkers and coworkers [29]. We think [29]. that,We think in our that, work, in our the work, reaction the proceeds reaction proceeds via a typical via a Skraup typical reaction Skraup mechanism,reaction mechanism, but with but glycerol with havingglycerol a having dual role a dual where role one where mol ofone glycerol mol of actsglycerol as a startingacts as a materialstarting reactingmaterial withreacting H2SO with4 to H produce2SO4 to acroleinproduce2 ,acrolein and another 2, and mol another of glycerol mol of acts glycerol as a catalyst acts as and a catalyst bounds and via H-bondbounds via with H-bond acroline with to generate acroline complexto generate9. This complex then undergoes9. This then a undergoes Michael addition a Michael with addition the aromatic with aminesthe aromatic (3a, b ).amines This is (3a, followed b). This by is the followed release ofby glycerol the release once of more glycerol to produce once more the intermediate to produce the4a, bintermediatethat then cyclizes 4a, b that to 6a thenand cyclizes6b, respectively. to 6a and 6b Scheme, respectively.4 shows Scheme a suggested 4 shows reaction a suggested mechanism reaction for themechanism formation for of the quinoline formation6a, of b .quinoline In our reaction 6a, b. In conditions, our reaction there conditions, were no needthere towere add no any need oxidizing to add agentsany oxidizing since we agents believe since that we concentrated believe that H concentrated2SO4 acts as a H condensation2SO4 acts as a agent condensation and an oxidant. agent and an oxidant.

Scheme 4. MechanismMechanism of ofour our modified-Skraup’s modiﬁed-Skraup’s synthesis synthesis of quinolines of quinolines under under high pressure high pressure using usingQ-tubes. Q-tubes.

A member of of our our group group investigated investigated the the x-ray x-ray structure structure of ofcompound compound 6b, 6b,which which confirmed conﬁrmed the thesuggested suggested structure, structure, and andno loss no lossof fluorine of ﬂuorine atom atomss occurred occurred under under our ourreaction reaction conditions conditions [65] [(Cf.65] (Cf.Figure Figure 1). The1). Thepreliminary preliminary inspection inspection of the of theX-ray X-ray crystallographic crystallographic data data of 6(b) of 6(b) indicated indicated that that the themolecules molecules exist exist in aggregates, in aggregates, via via intermolecul intermolecularar H-bonding H-bonding between between Fluorine Fluorine at at C-8 C-8 and and the hydrogen at C-8, as as well well as as between between N-1 N-1 and and H H at at C-4 C-4 (Cf. (Cf. Figure Figure 2).2). A A detailed detailed discussion discussion of of the the x- x-ray structure of these quinolines will be reported separately after exploring this phenomenon with other compounds. Molecules 2019, 24 FOR PEER REVIEW 6 Molecules 2019, 24 FOR PEER REVIEW 6 ray structure of these quinolines will be reported separately after exploring this phenomenon with otherMoleculesray structurecompounds.2019, 24 ,of 1806 these quinolines will be reported separately after exploring this phenomenon6 with of 14 other compounds.

Figure 1. X-ray crystal structure of 6,8-difluoroquinoline 6b. Figure 1. X-ray crystal structure of 6,8-diﬂuoroquinoline 6b. Figure 1. X-ray crystal structure of 6,8-difluoroquinoline 6b.

FigureFigure 2. 2. AggregatesAggregates of of 6,8-difluoroquinoline 6,8-difluoroquinoline 6b6b thatthat shows shows H-7 H-7 and and F-8 F-8 H-bonding. H-bonding. Figure 2. Aggregates of 6,8-difluoroquinoline 6b that shows H-7 and F-8 H-bonding. Subsequently, we shifted to utilizing glycerol in the synthesis of pyridazines. The pyridazine ring Subsequently, we shifted to utilizing glycerol in the synthesis of pyridazines. The pyridazine is an important structural feature in a number of pharmaceutical compounds, such as hydralazine ring isSubsequently, an important we structural shifted to feature utilizing in glycerol a number in the of synthesispharmaceutical of pyridazines. compounds, The pyridazinesuch as (brand name Apresoline, vasodilator, US, FDA), cefozopran (anti-bacterial agent, Japan), and pipofezine hydralazinering is an (brand important name structuralApresoline, feature vasodilator, in a US,number FDA), of cefozopran pharmaceutical (anti-bacterial compounds, agent, Japan),such as (brand name Azafen or Azaphen, antidepressant, STADA, Nizhny Novgorod, Russia). Pyridazine andhydralazine pipofezine (brand (brand name name Apresoline, Azafen vasodilator,or Azaphen, US, antidepressant, FDA), cefozopran STADA, (anti-bacterial Nizhny agent,Novgorod, Japan), Russia).derivativesand pipofezine Pyridazine have been(brand derivatives reported name have toAzafen possess been orreported variousAzaphe to pharmacologicaln, possess antidepressant, various activitiespharmacological STADA, and Nizhny intermediates activities Novgorod, and for intermediatesdrugsRussia). synthesis, Pyridazine for includingdrugs derivatives synthesis, antimicrobial, have including been analgesic, reported antimicrobial, anticancer, to possess analgesic, antitubercular,various pharmacological anticancer, antidiabetic, antitubercular, activities antifungal, and antidiabetic,antihypertensive,intermediates antifungal, for anticonvulsant, drugs antihypertensive, synthesis, anti-HIV, including anticonvulsant, antiasthma, antimicrobial, anti-inflammatory, anti-HIV, analgesic, antiasthma, anticancer, phosphodiesterase anti-inflammatory, antitubercular, (PDE) phosphodiesteraseinhibitors,antidiabetic, cyclooxygenase antifungal, (PDE) antihypertensive,inhibitors, (COX) inhibitors, cyclooxygenase anticonvulsant, antipyretic, (COX) insecticidal, anti-HIV,inhibitors, antiasthma, andantipyretic, neurological anti-inflammatory, insecticidal, [66–73]. and The 10d 11b neurologicalreactionphosphodiesterase of arylazo [66–73]. (PDE)Theand reaction inhibitors, ethylacetoacetate of arylazo cyclooxygenase 10d andin either ethylacetoacetate(COX) acetic inhibitors, acid or 11b ethanolicantipyretic, in either KOH, insecticidal, acetic followed acid andor by 15d ethanolicrefluxneurological to KOH, afford [66–73]. followed pyridazinones The by reaction reflux to, hasof afford arylazo been pyridazinones reported. 10d and Thisethylacetoacetate 15d reaction, has been was reported. limited11b in either toThis the reaction acetic formation acid was ofor 12d 12a limitedethanolic, and to wasthe KOH, formation not followed consistently of by 12d reflux successful, and to was afford andnot pyridazinones Trialsconsistently to form successful 15dfailed,, has been and since reported.Trials malononitrile to formThis reaction12a dimerized failed, was under these conditions [74,75]. In this case, we could efficiently prepare pyridazinones 13a–c in limited to the formation of 12d, and was not consistently successful and Trials to form 12a failed, good yields, by the reaction of malononitrile 11a, phenylhydrazono esters 10a–c, and glycerol, either

Molecules 2019, 24 FOR PEER REVIEW 7 Molecules 2019, 24, 1806 7 of 14 since malononitrile dimerized under these conditions [74,75]. In this case, we could efficiently prepare pyridazinones 13a–c in good yields, by the reaction of malononitrile 11a, phenylhydrazono under conventional heating at 250 ◦C for 5 h, or under pressure in the Q-tubes at 150 ◦C for 30 min esters 10a–c, and glycerol, either under conventional heating at 250 °C for 5 h, or under pressure in (cf. Scheme5). the Q-tubes at 150 °C for 30 min (cf. Scheme 5).

Scheme 5. Synthesis of 4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate 13a–c. Scheme 5. Synthesis of 4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate 13a–c. It was found that the yield of formation of 13a–c increased signiﬁcantly under reactions caused by pressure,It was Table found2 summarizes that the yield our of ﬁndings formation and of compares 13a–c increased these reaction significantly yields. under reactions caused by pressure, table 2 summarizes our findings and compares these reaction yields. Table 2. Reaction yield for 13a–c and 12d under pressure and conventional heating. Table 2. Reaction yield for 13a–c and 12d under pressure and conventional heating. Yield Percentage Product x y z Yield Percentage Product x y z Conventional Under Conventional HeatingHeating Under PressurePressure

13a 13a CNCN COOCH COOCH2Ph2Ph H H 52 52 76 76 13b CN COOEt CN 64 88 13b CN COOEt CN 64 88 13c COOEt COOEt H 70 92 12d 13c CNCOOEt COOEt H H CH3 70 86.16 [74]- 92

12d CN H CH3 86.16 [74] - We assume that glycerol acts as a catalyst and a bio-based solvent. The catalytic activity of We assume that glycerol acts as a catalyst and a bio-based solvent. The catalytic activity of glycerol in this reaction might be via H-bond formation with the N-atom in compound 11, to form glycerol in this reaction might be via H-bond formation with the N-atom in compound 11, to form the intermediate 14. The H-bond formation facilitates the Michael-type addition of the active the intermediate 14. The H-bond formation facilitates the Michael-type addition of the active methylene of the arylazo 10 on the even more electron-poor CN carbon forming the protonated imine methylene of the arylazo 10 on the even more electron-poor CN carbon forming the protonated imine 15. It is suggested that another mole of glycerol coordinates with protonated imines 15, followed 15. It is suggested that another mole of glycerol coordinates with protonated imines 15, followed by by an intramolecular cyclization and glycerol is released again to the medium, which aﬀords the an intramolecular cyclization and glycerol is released again to the medium, which affords the 4-oxo- 4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate13a–c. Scheme6 shows our suggested 1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate13a–c. Scheme 6 shows our suggested mechanism for mechanism for the formation of 13a–c. the formation of 13a–c.

Molecules 2019, 24, 1806 8 of 14 Molecules 2019, 24 FOR PEER REVIEW 8

Scheme 6.6. MechanismMechanism of of synthesis synthesis of 4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate of 4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate13a–c. 13a–c. The structures of compounds 13a–c were conﬁrmed by spectroscopic analysis. Compound 13a had 1 an mThe/z value structures of 362.53. of compounds The H NMR 13a–c spectrum were of confirmed13a revealed by twospectroscopic multiplets analysis. for the prochiral Compound CH2 -CN13a hadat δ =an1.28 m/z and value 1.31 of ppm. 362.53. A twoThe multiplets1H NMR spectrum for the prochiral of 13a revealed ring methylene two multiplets protons for COCH the 2prochiralappears CHat δ2-CN= 2.39 at andδ = 1.28 2.49 and ppm. 1.31 A singletppm. A at twoδ = multiplets4.30 ppm is for assigned the prochiral for two ring methylene methylene protons, protons a multiplet COCH2 appearsat δ = 7.10 at ppmδ = 2.39 for and the aromatic2.49 ppm. 10H, A singlet and two at δ singlets = 4.30 ppm for the is fourassigned NH2 forprotons two methylene at δ = 11.56 protons, ppm and a 13 multiplet14.22 ppm, at respectively.δ = 7.10 ppmThe for theC-NMR aromatic spectrum 10H, and of two compound singlets13a for showedthe four aNH signal2 protons at δ = at196.8 δ = 11.56 ppm ppmsigniﬁcant and 14.22 for a ppm, true carbonyl, respectively. assigned The 13 toC-NMR the pyridazine spectrum ring of carbonyl,compound and 13a showed showed another a signal signal at δ at= 196.8δ = 163.4 ppm ppm significant for the ester for a carbonyl. true carbonyl, The CH assigned2CN methylene to the carbonpyridazine appears ring at carbonyl,δ = 25.9 ppm. and showed Figure3 13 anotherindicates signal the most at δ important= 163.4 ppmC-NMR for the ester signals carbonyl. for 13a. The CH2CN methylene carbon appears at δ = 25.9 ppm. Figure 3 indicates the most important 13C-NMR signals for 13a.

Molecules 2019, 24, 1806 9 of 14 Molecules 2019, 24 FOR PEER REVIEW 9

O O

63.5 163.4 196.8 O 60.8

25.9 N 72.9 116.6 N NH2 N

Figure 3. 13C-NMR spectroscopic analysis of 13a. Figure 3. 13C-NMR spectroscopic analysis of 13a. 3. Materials and Methods 3. Materials and Methods 3.1. General 3.1. General Q-tube assisted reactions were performed in a Q-tube safe pressure reactor from Q Labtech (East Lyme,Q-tube CT 06333, assisted New reactions London County,were performed CT, USA, in equipped a Q-tube with safe apressure cap/sleeve, reactor pressure from adapter Q Labtech (120 (East psi), needleLyme, CT adapter 06333,/needle, New London borosilicate County, glass CT, tube, USA, Teﬂon equipped septum, with and a cap/sleeve, catch bottle. pressure All reactions adapter were (120 monitoredpsi), needle by adapter/needle, using TLC with borosilicate 1:1 ethyl acetate-petroleum glass tube, Teflon ether septum, as eluent and andcatch were bottle. carried All reactions out until startingwere monitored materials by were using completely TLC with 1:1 consumed. ethyl acetate-petroleum Melting points ether are reported as eluent uncorrected and were carried and were out determineduntil starting with materials a Sanyo were (Gallenkamp, completely Osaka, consumed. Japan). Melting1H NMR points and are13C-NMR reported spectra uncorrected were done and atwere the determined Analab Kuwait with University a Sanyo (Gallenkamp, and determined Osaka, by using Japan). a Bruker 1H NMR DPX and instrument 13C-NMR at spectra 600 MHz were for 1 13 doneH-NMR at the and Analab 150 MHz Kuwait for UniversityC-NMR andand eitherdetermined CDCl 3byor using DMSO- a Brukerd6 solutions DPX instrument with TMS at as 600 internal MHz standards.for 1H-NMR Chemical and 150 MHz shifts for are 13 reportedC-NMR and in δ either(ppm). CDCl Mass3 or spectra DMSO- andd6 solutions accurate with mass TMS measurements as internal werestandards. made Chemical using a GCMS shifts DFSare reported spectrometer in δ (Thermo,(ppm). Mass Bremen, spectra Germany) and accurate with themass EI measurements (70 EV) mode. X-raywere made crystallographic using a GCMS structure DFS spectrometer determinations (Thermo, were performedBremen, Germany) by using with Rapid the II EI (Rigaku, (70 EV) Tokyo,mode. Japan)X-ray crystallographic and X8 Prospector structure (Bruker, determinations Karlsruhe, Germany) were performed single crystal by using X-ray Rapid diﬀractometers. II (Rigaku, Tokyo, Japan) and X8 Prospector (Bruker, Karlsruhe, Germany) single crystal X-ray diffractometers. 3.2. General Procedures for Q-Tube-Assisted Synthesis of Quinolines 6a,b

3.2. GeneralGlycerol Procedures1 (5 mL), for concentrated Q-Tube-Assisted sulfuric Synthesis acid (1 of mL),Quinolines and 0.01 6a,b mol of the corresponding aniline (0.93Glycerol g 3a or 1.29 1 (5 gmL), of 3 concentratedb) were sequentially sulfuric addedacid (1 inmL), a 35 and mL 0.01 Q-tube mol of pressure the corresponding tube, furnished aniline by Q(0.93 Labtech. g 3a or A 1.29 Teflon g ofseptum 3b) were was sequentially placed on added top of in the a tube,35 mL and Q-tube an appropriate pressure tube, cap furnished was used. by The Q mixtureLabtech. wasA Teflon heated septum in an oil was bath placed at 200 on◦C top for of about the tube, 60 min. and The an mixtureappropriate was cooledcap was and used. poured The intomixture ice-water. was heated The solidin an wasoil bath collected at 200 by °C filtration for about and 60 purifiedmin. The bymixture column was chromatography cooled and poured and crystallizedinto ice-water. from The ethanol. solid was collected by filtration and purified by column chromatography and crystallized from ethanol. 3.3. 6,8-Difloroquinoline 6b 3.3. 6,8-Difloroquinoline 6b 1 Yellow crystals, yield 60%, mp >250 ◦C, H-NMR (DMSO-d6, 600 MHz): δ = 7.62–7.70 (3H, m, 13 1 d δ H-3, H-5,Yellow H-7), crystals, 8.38 (1H, yield m, 60%, H-4), mp 8.90 >250 (1H, °C, t, H-2).H-NMRC-NMR (DMSO- (150d6, MHz,600 MHz): DMSO- δ = 67.62–7.70): = 105.12, (3H,107.13, m, H- 13 m z 123.37,3, H-5, 129.23,H-7), 8.38 135.04, (1H, 150.16, m, H-4), 156.90, 8.90 157.75, (1H, t, 158.61, H-2). 159.38.C-NMR EI-HRMS: (150 MHz,/ DMSO-for C9Hd56F):2 δN, = calcd.105.12, 165.0390, 107.13, found:123.37, 165.0384.129.23, 135.04, 150.16, 156.90, 157.75, 158.61, 159.38. EI-HRMS: m/z for C9H5F2N, calcd. 165.0390, found: 165.0384. 3.4. General Procedure to Aniline Trimers 7 and 8 3.4. GeneralA 35 mL Procedure Q-tube pressureto Aniline tube, Trimers furnished 7 and 8 by Q Labtech was charged with aniline derivative 3c-e (10 mmol) (2.23 g of 3c, 1.86 g of 3d, 1.41 g of 3e), 5 mL glycerol, 3 mL H SO , and 10 mL of water. A 35 mL Q-tube pressure tube, furnished by Q Labtech was charged 2with4 aniline derivative 3c- A Teflon septum was placed on top of the tube, and an appropriate cap was used. The mixture was e (10 mmol) (2.23 g of 3c, 1.86 g of 3d, 1.41 g of 3e), 5 mL glycerol, 3 mL H2SO4, and 10 mL of water. heated in an oil bath at 160 C for 15 min. After cooling at room temperature, pH was adjusted at 8–9 A Teflon septum was placed◦ on top of the tube, and an appropriate cap was used. The mixture was by adding NaOH and the reaction mixture was extracted with ethyl acetate (2 20 mL). The combined heated in an oil bath at 160 °C for 15 min. After cooling at room temperature,× pH was adjusted at 8– 9 by adding NaOH and the reaction mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over MgSO4 and were then filtered and evaporated under

Molecules 2019, 24, 1806 10 of 14

organic layers were dried over MgSO4 and were then ﬁltered and evaporated under reduced pressure. The crude residue was puriﬁed by column chromatograph (cyclohexane–EtOAc) on silica gel yielding the corresponding quinoline.

3.4.1. 4,40,4”-(propane-1,2,3-triyl)tris(2-methylaniline) 7 1 Yellow crystals yield 75%. mp 178–180 ◦C, H-NMR (DMSO-d6, 600 MHz) : δ = 2.00 (9H,s, 3-CH3), 3.34 (5H, m, 2CH2 and CH aliphatic), 5.01 (6H, s, 3NH2), 6.42 (3H, d, Ar-H), 7.13–7.20 (6H, m, Ar-H), 13 C-NMR (150 MHz, DMSO-d6): δ = 16.95 (3CH3), 74.0 (CH-aliphatic), 76.24 (2CH2-aliphatic), 116.27 (3 ortho-C), 124.21 (3C-CH3), 134.63 (6 meta-C), 137.55 (3para-C), 146.53 (3C-NH2). EI-HRMS: m/z for C24H29N3, calcd. 359.2361, found: 359.2362.

3.4.2. 4-(2-(4-amionphenoxy)-3-(4-amoinophenoxy))aniline 8

1 Brown crystals, yield 72%. mp 240 ◦C. H-NMR (DMSO-d6, 600 MHz): δ = 2.49 (6H, s, 3NH2), 3.27 (2H, d, J = 6 Hz, CH2), 3.29 (2H, d, J = 6 Hz, CH2), 3.35 (1H, m, CH), 6.94-7.26 (14H, m, Ar-H). 13 C-NMR (150 MHz, DMSO-d6): δ = 63.09 (2C, CH2), 72.49 (CH), 118.57 (3C, C-NH2), 122.01 (2C-O), 129.32 (12C, Ar-C), 140.07 (C-O), EI-HRMS: m/z for C21H23N3O3; calcd. 365.1739; found: 365.1736.

3.5. General Procedure for Syntheses of 13a–c

3.5.1. Method A: Conventional Heating A mixture of 0.01 mol of the appropriate azo compound 10a–c (10a, 2.96 g, 10b, 2.59 g, 10c, 2.34 g) is added to 11a (0.66 g, 0.01 mol) in glycerol (5 mL). The reaction mixture was reﬂuxed for 3–5 h (followed until completion by TLC using 1:1 ethyl acetate- petroleum ether as an eluent). The mixture was cooled and then was poured onto ice-water. The solid, so formed, was collected by ﬁltration and recrystallized from EtOH.

3.5.2. Method B: Q-Tube Assisted Reactions A 35 mL Q-tube pressure tube, furnished by Q Labtech was charged with 0.01 mol of the appropriate azo compound 10a–c (2.96 g of 10a, 2.59 g of 10b, 2.34 g of 10c), (0.66 g, 0.01 mol) of malononitrile 11a and 5mL glycerol. A Teﬂon septum was placed on top of the tube, and an appropriate cap was used. The mixture was heated at 150 ◦C for 30 min followed until completion by TLC using 1:1 ethyl acetate-petroleum ether as an eluent. The mixture was cooled and then was poured onto ice-water. The solid, so formed, was collected by ﬁltration and recrystallized from EtOH.

3.6. Benzyl 6-amino-6-(cyanomethyl)-4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate 13a

1 Yellow crystals, yield 52% (method A), 76% (method B); mp >340 ◦C. H-NMR (DMSO-d6, 600 MHz): δ = 1.28,1.31 (2H, m, CH2), 2.39,2.49 (2H, CH2, m), 4.30 (2H, s, CH2), 7.10–7.53 (10H, m, 13 2-Ph), 11.56, 14.22 (2H, 2s, NH2). C-NMR (150 MHz, DMSO-d6): δ = 196.8 (C=O), 164.5 (C=O), 163.0 (N-C-Ar), 142.8 (N=C), 132.0 (2C-Ar), 131.2 (3C-Ar), 129.8 (2C-Ar), 125.8 (2C-Ar), 116.6 (CN), 115.6 (2C-Ar), 72.9 (C-NH2), 60.8 (CH2-O), 30.8 (CH2), 25.9 (CH2). HRMS: m/z (EI) for C20H18N4O3, calcd. 362.1379, found: MS: m/z (%) = 362.53 (M+).

3.7. Ethyl-6-amino-5-cyano-6-(cyanomethyl)-4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate 13b

Red crystals, yield 64% (method A), 88% (method B); m.p. 256-258 ◦C, IR (KBr): 3425 (NH), 2202 1 1 (CN), 1620 (CO) cm− , H-NMR (DMSO-d6, 600 MHz): δ = 1.04 (3H,t, CH3), 1.05 (2H,m, CH2), 2.03 (1H,s, 13 CH), 3.33 (2H,s, CH2), 4.32 (2H,m, CH2), 7.27-7.64 (5H, m, H-Ph). C-NMR (150 MHz, DMSO-d6)): δ = 13.90 (CH3), 24.0 (C-CN), 26.69 (CH2), 61.23 (C-O), 66.0 (C-NH2), 115.90 (2C; 2CN), 119.21 (2C-Ar), 123.87 (C-Ar), 128.88 (2C-Ar), 129.51 (C=N), 138.34 (C-Ar), 160.97 (2C=O). MS (EI): m/z = 326.0 (M+). + HRMS: m/z (EI) for C16H15N5O3, calcd. 325.1175, found: MS: m/z (%) = 326.0 (M ). Molecules 2019, 24, 1806 11 of 14

3.8. Ethyl-6-amino-6-(2-ethoxy-2-oxoethyl)-4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate 13c

Brown crystals, yield 70% (method A), 92% (method B), m.p. 266–268 ◦C, IR (KBr): 3439 (NH), 1 1 2222 (CN), 1670 (CO) cm− , H-NMR (DMSO-d6, 600 MHz) : δ = 1.20 (3H,t, CH3), 1.40 (3H,t, CH3), 2.50 (2H,s, CH2), 3.36 (2H,s, CH2), 4.10 (2H,m, CH2), 4.35 (2H,m, CH2), 7.07-7.55 (5H, m, H-Ph), 10.29 13 (1H, s, NH). C-NMR (150 MHz, DMSO-d6): δ = 8.37 (2C- CH3), 62.59 (CH2), 63.06 (CH2), 66.24 (CH2-O), 68.81 (CH2-O), 72.48 (C-NH2), 114.96 (C-Ar), 116.15 (CN), 116.30 (C-Ar), 123.62 (C-Ar), 129.05 (C-Ar), 129.62 (C-Ar), 130.16 (C=N), 142.42 (C=O), 161.72 (C=O), 196.22 (C=O). HRMS: m/z (EI) for + C17H21N3O5: 347.1481, found: MS: m/z (%) = 347.1 (M ).

4. Conclusions In this study, we combined glycerol and water as green, efficient solvents, in addition to pressure in Q-tubes, to modify the synthesis of quinolines and prepare new aniline trimers and pyridazines. Glycerol was efficiently employed either as a catalyst or a reactant and green bio-based solvent in the synthesis of novel quinolines, aniline trimers, and pyridazines. The dual use of glycerol along with reactions under pressure proved its efficiency as a green method for synthesis of quinolines as reactions products were obtained in higher yields, shorter time, and without any oxidizing agents. Reactions of anilines, sulphuric acid, water, and glycerol under pressure allowed for the synthesis of unexpected novel aniline trimers. Lastly, glycerol also proved to be an efficient medium/catalyst for synthesis of novel pyridazines in very good yields under pressure. Future perspectives for this work are various since our techniques should open the appetite of researchers to extend this work for the synthesis of azoles, azines, and other polyanilines.

Author Contributions: Conceptualization, N.M.H.E. Data curation, D.S.A. Investigation, N.M.H.E. and D.S.A. Methodology, N.M.H.E. Resources, D.S.A. Supervision, N.M.H.E. Writing—original draft, N.M.H.E. Writing—review & editing, N.M.H.E and D.S.A. Funding: This research received no external funding. Acknowledgments: The authors would like to express their deepest gratitude and acknowledgment for M. H. Elnagdi Emeritus Professor at Cairo University, Cairo, Egypt, for his valuable scientific consultations, guidance, and valuable criticism throughout this work. Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 22a–c are available from the authors.

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