Synthesis and Fluorescent Properties of Novel Isoquinoline Derivatives

molecules

Article Synthesis and Fluorescent Properties of Novel Isoquinoline Derivatives

1, 1, 2 1 Łukasz Balewski * , Franciszek S ˛aczewski †, Maria Gdaniec , Anita Kornicka , Karolina Cicha 1 and Aleksandra Jali ´nska 1

1 Department of Chemical Technology of Drugs, Faculty of Pharmacy, Medical University of Gdańsk, 80-416 Gdańsk,Poland; [email protected] (F.S.); [email protected] (A.K.); [email protected] (K.C.); [email protected] (A.J.) 2 Faculty of Chemistry, Adam Mickiewicz University, 61-614 Poznań,Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-58-349-1952; Fax: +48-58-349-1654 Deceased 18 October 2018. † Received: 26 September 2019; Accepted: 8 November 2019; Published: 10 November 2019

Abstract: Isoquinoline derivatives have attracted great interest for their wide biological and fluorescent properties. In the current study, we focused on the synthesis of a series of novel isoquinoline derivatives substituted at position 3 of the heteroaromatic ring. Compounds were obtained in a Goldberg–Ullmann-type coupling reaction with appropriate amides in the presence of copper(I) iodide, N,N-dimethylethylenediamine (DMEDA), and potassium carbonate. The structures of novel isoquinolines were confirmed by IR, nmR, and elemental analysis, as well as X-ray crystallography. In the course of our research work, the visible fluorescence of this class of compounds was observed. The above findings prompted us to investigate the optical properties of the selected compounds.

Keywords: isoquinoline derivatives; copper-catalyzed coupling; ﬂuorescence; X-ray crystallography

1. Introduction Among heteroaromatic compounds, the isoquinoline (benzo[c]pyridine) scaffold constitutes an important and privileged structural framework, and may be found in several naturally occurring alkaloids [1,2]. Biological activities of isoquinoline derivatives found in nature, as well as those obtained by organic synthetic procedures, have been widely explored. Isoquinoline compounds possess antihypertensive, anti-inflammatory, anti-oxidant, antipyretic, and analgesic properties [3– 5]. It was also demonstrated that isoquinoline derivatives exhibit antifungal, antibacterial [6], and anti-malarial activities [7]. In addition, it was found that isoquinolines may act as antidepressants and antipsychotic agents [8]. Several compounds with isoquinoline core were found to exhibit anti-tumor or antiproliferative activity serving as a lead structure for the development of potential anticancer drugs [9–12]. Noteworthy is the fact that the isoquinoline ring constitutes an important molecular part of topical anesthetic drug quinisocaine, whereas the 1,2,3,4-tetrahydroisoquinoline moiety is found in the structure of antihypertensive drugs, quinapril and debrisoquine. An inspection of the literature data indicates that isoquinoline-3-amine derivatives exhibit fluorescent properties and may constitute potential fluorophores [13–15]. Moreover, for many years the electronic states and optical properties of isoquinoline and its derivatives have been an object of particular interest and study [16–25]. Recently, notable progress has been made in the synthesis and development of novel organic fluorophores with diverse applications and uses in in vivo imaging. Derivatives with high extinction coefficients, long absorption wavelengths, high quantum yields of fluorescence, and high fluorescence lifetimes may be obtained by molecular design [26].

Molecules 2019, 24, 4070; doi:10.3390/molecules24224070 www.mdpi.com/journal/molecules Molecules 2019, 24, 4070 2 of 16 MoleculesMolecules 20192019,, 2424,, xx FORFOR PEERPEER REVIEWREVIEW 22 ofof 1616

2.2. Results Results and and Discussion Discussion

2.1.2.1. Synthesis Synthesis of of 1-(Isoquinolin-3-yl)heteroalkyl(aryl)-2-ones 1-(Isoquinolin-3-yl)heteroalkyl(aryl)-2-ones 3a3a---ddd andandand 1,3-di(Isoquinolin-3-yl)heteroalkyl(aryl)-2-ones1,3-di(Isoquinolin-3-yl)heteroalkyl(aryl)-2-ones1,3-di(Isoquinolin-3-yl)heteroalkyl(aryl)-2-ones 4a 4a4a--c-cc NovelNovel isoquinolineisoquinoline isoquinoline derivativesderivatives derivatives werewere were obtainedobtained obtained accordingaccording according toto copper-catalyzedcopper-catalyzed to copper-catalyzed Goldberg–Goldberg– Goldberg–Ullmann-typeUllmann-typeUllmann-type couplingcoupling couplingofof arylaryl ofhalideshalides aryl halides withwith with2-imidazolidinone2-imidazolidinone 2-imidazolidinone [27,28].[27,28]. [27,28 ].TheThe The reactionsreactions reactions ofof 3-bromoisoquinoline3-bromoisoquinoline ( 1((1)1)) with withwith azetidin-2-one azetidin-2-oneazetidin-2-one (2a ((),2a2a pyrrolidin-2-one),), pyrrolidin-2-onepyrrolidin-2-one (2b ),((2b2b 3-methylpyrrolidin-2-one),), 3-methylpyrrolidin-2-one3-methylpyrrolidin-2-one (2c), and((2c2c),), piperidin-2-one andand piperidin-2-onepiperidin-2-one (2d) were ((2d2d)) carried werewere carriedcarried out in theoutout presence inin thethe presencepresence of anhydrous ofof anhydrousanhydrous potassium potassiumpotassium carbonate, carbonate,carbonate, copper(I) iodidecopper(I)copper(I) (CuI), iodideiodide and N(CuI),(CuI),,N-dimethylethylenediamine andand NN,,NN-dimethylethylenediamine-dimethylethylenediamine (DMEDA) as (DMEDA)(DMEDA) a ligand, a ﬀasasording aa ligand,ligand, the corresponding affordingaffording thethe 1-(isoquinolin-3-yl)heteroalkyl-2-onescorrespondingcorresponding 1-(isoquinolin-3-yl)heteroalkyl-2-ones1-(isoquinolin-3-yl)heteroalkyl-2-ones3a-d (Scheme1). 3a3a--dd (Scheme(Scheme 1).1).

SchemeScheme 1.1. SynthesisSynthesis of of 1-(isoquinolin-3-yl)heteroalkyl-2-ones1-(isoquinolin-3-yl)heteroalkyl-2-ones 3a3a––dd.d..

InIn turn,turn,turn, thethethe useuseuse ofofof imidazolidin-2-oneimidazolidin-2-oneimidazolidin-2-one ((2e(2e2e),),), 111HHH-benzimidazol-2(3-benzimidazol-2(3-benzimidazol-2(3HH)-one)-one (((2f2f2f),),), oror 5-methoxy-15-methoxy-1HH-benzimidazol-2(3-benzimidazol-2(3HH)-one)-one)-one (( (2g2g))) asas the the substrate substrate allowedallowed obtainingobtaining thethe targettargettarget 1-(isoquinolin-3-yl)heteroalkyl(aryl)-2-ones1-(isoquinolin-3-yl)heteroalkyl(aryl)-2-ones1-(isoquinolin-3-yl)heteroalkyl(aryl)-2-ones 3e3e––hh (major(major products)products) andand thethethe correspondingcorrespondingcorresponding 1,3-disubstituted1,3-disubstituted1,3-disubstituted derivativesderivativesderivatives 4a 4a4a–––ccc (minor (minor(minor products)products)products) (Scheme (Scheme(Scheme2 2).).2).

Scheme 2. Synthesis of 1-(isoquinolin-3-yl)heteroalkyl(aryl)-2-ones 3e–h and 1,3-di(isoquinolin-3-yl) heteroalkyl(aryl)-2-onesSchemeScheme 2.2. SynthesisSynthesis4a–c . ofof 1-(isoquinolin-31-(isoquinolin-3-yl)heteroalkyl(aryl)-2-ones-yl)heteroalkyl(aryl)-2-ones 3e3e––hh andand 1,3-di(isoquinolin-3-yl)heteroalkyl(aryl)-2-ones1,3-di(isoquinolin-3-yl)heteroalkyl(aryl)-2-ones 4a–c.4a–c. The formation of the ﬂuorescent product was controlled by sampling the reaction mixture for thin-layerTheThe formationformation chromatography ofof thethe fluorescentfluorescent when the product reactionproduct was co expectedcontrolledntrolled to byby be samplingsampling completed thethe (3 reactionreaction to 85 h). mixturemixture After theforfor requiredthin-layerthin-layer time, chromatographychromatography mixtures were whenwhen cooled thethe toreactionreaction room temperaturewaswas expectedexpected and toto bebe diluted completedcompleted with chloroform(3(3 toto 8585 h).h). followedAfterAfter thethe requiredrequired time,time, mixturesmixtures werewere coolcooleded toto roomroom temperaturetemperature andand diluteddiluted withwith chloroformchloroform followedfollowed byby

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Molecules 2019, 24, x FOR PEER REVIEW 3 of 16 by filtration. Products were separated by preparative thin-layer chromatography (chromatotron). Wefiltration. began by Products studying were the separated catalyticcoupling by preparativ reactione thin-layer of 3-bromoisoquinoline chromatography with (chromatotron). imidazolidin-2-one We began by studying the catalytic coupling reaction of 3-bromoisoquinoline with imidazolidin-2-one at at different temperatures and various solvents, such as toluene, tetrahydrofuran, dimethylformamide, different temperatures and various solvents, such as toluene, tetrahydrofuran, dimethylformamide, n-butanol, and 1,4-dioxane. It was found that the higher conversion of starting materials and better n-butanol, and 1,4-dioxane. It was found that the higher conversion of starting materials and better yields of desired products were achieved using n-butanol as a solvent. Reactions using cesium carbonate yields of desired products were achieved using n-butanol as a solvent. Reactions using cesium instead of potassium carbonate as a base were unsuccessful. Synthesis of 3a required anhydrous carbonate instead of potassium carbonate as a base were unsuccessful. Synthesis of 3a required 2a 1,4-dioxaneanhydrous at1,4-dioxane 90 ◦C, due toat limited90 °C, stabilitydue to oflimited the substrate stability of. The the use substrate of dimethylformamide 2a. The use of as a solventdimethylformamide had a negative as e ffa ectsolvent on the had purity a negative and further effect isolation on the purity of the and desired further products. isolation of the desiredIn our products. study, we found that for the 1-(isoquinolin-3-yl)heteroalkyl(aryl)-2-ones a stoichiometric ratio ofIn theour reactants study, we in found terms that of yieldsfor the and1-(isoquinolin-3-yl)heteroalkyl(aryl)-2-ones purity was the most important factor. a In stoichiometric the synthesis of 3bratio, 3d ,of3f the, 3g reactants, 3h, and in4a terms–c, a of three-fold yields and excess purity of was compound the most 2importantgave the factor. best result. In the Thesynthesis equimolar of ratio3b, 3d of, substrates3f, 3g, 3h, and1 and 4a–2ac, ain three-fold 1,4-dioxane excess was of usedcompound in the 2 synthesisgave the best of 3a result.giving The the equimolar product in 61%ratio yield. of substrates On the other1 and hand,2a in 1,4-dioxane the highest was yield used of in the the product synthesis3e wasof 3aachieved giving the in product the presence in 61% of a five-foldyield. On excess the other of compound hand, the2e highest(reaction yield time of 3the h). product Importantly, 3e was a longer achieved reaction in the time presence resulted of ina an increasingfive-fold excess amount of compound of 1,3-di(isoquinolin-3-yl)imidazolidin-2-one 2e (reaction time 3 h). Importantly, a (longer4a), even reaction though time a largeresulted excess in of imidazolidin-2-onean increasing amount (2e )of was 1,3-di(isoquinolin-3-yl)imidazolidin-2-one used. (4a), even though a large excess of imidazolidin-2-oneThe lowest reactivity (2e) was was used. observed in the case of the benzimidazole derivatives 2f and 2g, The lowest reactivity was observed in the case of the benzimidazole derivatives 2f and 2g, and and the yields were diminished (5–18% yield, 80 or 85 h heating at 100 ◦C). Reaction involving the yields were diminished (5–18% yield, 80 or 85 h heating at 100 °C). Reaction involving 1-isopropenyl-2-benzimidazolidione under the same conditions (100 ◦C, 85 h) provided no product. Furthermore,1-isopropenyl-2-benzimidazolidione the reaction of 1 with 5-methoxy-1under the sameH-benzimidazol-2(3 conditions (100 °C,H 85)-one h) provided (2g) afforded no product. a mixture ofFurthermore, the two isomeric the reaction products: of 1 1-(isoquinolin-3-yl)-5-methoxy-1with 5-methoxy-1H-benzimidazol-2(3H-benzimidazol-2(3H)-one (2g) affordedH)-one a mixture (3g) and of the two isomeric products: 1-(isoquinolin-3-yl)-5-methoxy-1H-benzimidazol-2(3H)-one (3g) and 1-(isoquinolin-3-yl)-6-methoxy-1H-benzimidazol-2(3H)-one (3h). Due to difficulties associated with 1-(isoquinolin-3-yl)-6-methoxy-1H-benzimidazol-2(3H)-one (3h). Due to difficulties associated with purification, compounds 3g and 3h could not be isolated in pure form by chromatographic methods. purification, compounds 3g and 3h could not be isolated in pure form by chromatographic methods. The 1H nmR spectrum revealed the 1:1 ratio of the isomers 3g and 3h. The 1H NMR spectrum revealed the 1:1 ratio of the isomers 3g and 3h. 2.2. Synthesis of 1-(Isoquinolin-3-yl)-3-methylimidazolidin-2-one (5) and 1-(Isoquinolin-3-yl)-3-(hetero)aryl-2-ones2.2. Synthesis of 1-(Isoquinolin-3-yl)-3-methylimidazolidin-2-one7a-d (5) and 1-(Isoquinolin-3-yl)-3-(hetero)aryl-2-ones 7a-d The reaction of 1-(isoquinolin-3-yl)-3-imidazolidin-2-one (3e) with methyl iodide and solid The reaction of 1-(isoquinolin-3-yl)-3-imidazolidin-2-one (3e) with methyl iodide and solid sodium hydroxide in dimethylformamide at room temperature gave N-methyl derivative 5 in moderate sodium hydroxide in dimethylformamide at room temperature gave N-methyl derivative 5 in yield. Treatment of compound 3e with aryl or heteroaryl iodides in the presence of copper(I) iodide, moderate yield. Treatment of compound 3e with aryl or heteroaryl iodides in the presence of N,N’-dimethylethylenediamine, and potassium carbonate in n-butanol at 100 C gave corresponding copper(I) iodide, N,N’-dimethylethylenediamine, and potassium carbonate in ◦n-butanol at 100 °C 1-(isoquinolin-3-yl)-3-(hetero)aryl-2-onesgave corresponding 1-(isoquinolin-3-yl)-3-(hetero)aryl-2-ones7a–d (Scheme3). 7a–d (Scheme 3).

Scheme 3. Synthesis of 1-(isoquinolin-3-yl)-3-methylimidazolidin-2-one (5) and 1-(isoquinolin-3-yl)-3- (hetero)aryl-2-onesScheme 3. Synthesis7a–d. of 1-(isoquinolin-3-yl)-3-methylimidazolidin-2-one (5) and 1-(isoquinolin-3-yl)-3-(hetero)aryl-2-ones 7a–d.

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Molecules 2019, 24, x FOR PEER REVIEW 4 of 16 2.3. Synthesis of n-Butyl 3-(isoquinolin-3-ylamino)propanoate (8) and 3-(Isoquinolin-3-ylamino)-1-(pyrrolidin-1-yl)propan-1-one2.3. Synthesis of n-Butyl 3-(isoquinolin-3-ylamino)propanoate (9 ()8) and 3-(Isoquinolin-3-ylamino)-1-(pyrrolidin-1-yl)propan-1-one (9) It was found that the reaction of 3-bromoisoquinoline (1) with azetidin-2-one (2a) carried out It was found that the reaction of 3-bromoisoquinoline (1) with azetidin-2-one (2a) carried out at at 100 ◦C in n-butanol led to the formation of the n-butyl 3-(isoquinolin-3-ylamino)propanoate 100 °C in n-butanol led to the formation of the n-butyl 3-(isoquinolin-3-ylamino)propanoate (8) as 8 ( ) asshown shown in in Scheme Scheme 4.4 .The The reaction reaction consists consists of ofthree three mechanistic mechanistic steps: steps: formation formation of of 1-(isoquinolin-3-yl)azetidin-2-one1-(isoquinolin-3-yl)azetidin-2-one ( 3a(3a),), followedfollowed by by nucleophilic nucleophilic 1,2-addition 1,2-addition of the ofsolvent the solventto the to the carbonylcarbonyl group group of the ofβ the-lactam β-lactam ring. ring. Finally, Finally,n n-butyl-butyl esterester 88 isis formed formed asas a result a result of ring-opening of ring-opening of of the unstablethehemiacetal, unstable hemiacetal, followed followed by [1.3] by proton[1.3] proton shift. shift. In In addition, addition, compound compound 88 heatedheated under under reflux reﬂux with an excesswith of an pyrrolidine excess of pyrrolidine in ethanol in gaveethanol amide gave 9amidein moderate 9 in moderate yield yield (Scheme (Scheme4). It 4). should It should be notedbe that noted that in the proposed mechanism, the formation of fluorescent β-lactam 3a was observed. The in the proposed mechanism, the formation of ﬂuorescent β-lactam 3a was observed. The compound 3a compound 3a was detected by sampling the reaction mixture for thin-layer chromatography and was detectedHPLC. by sampling the reaction mixture for thin-layer chromatography and HPLC.

Scheme 4. Synthesis of n-butyl 3-(isoquinolin-3-ylamino)propanoate (8) and 3-(isoquinolin-3- Scheme 4. Synthesis of n-butyl 3-(isoquinolin-3-ylamino)propanoate (8) and ylamino)-1-(pyrrolidin-1-yl)propan-1-one (9). 3-(isoquinolin-3-ylamino)-1-(pyrrolidin-1-yl)propan-1-one (9).

The structuresThe structures of novel of novel isoquinoline isoquinoline derivative derivativess were were confirmed confirmed by IR byand IR NMR and spectroscopic nmR spectroscopic data, massdata, mass spectrometry, spectrometry, and and elementary elementary analysis.analysis. Moreover, Moreover, the thecrystal crystal structure structure of compound of compound 3e 3e was determinedwas determined by X-ray by X-ray crystallography. crystallography. The The molecule molecule of of3e 3e, as, as shown shown in in Figure Figure1 ,1, adopts adopts aa strongly flattenedstrongly conformation flattened conformation with the isoquinoline with the isoquinoline N atom oriented N atomtrans orientedrelative trans to therelative 2-imidazolidinone to the carbonyl2-imidazolidinone oxygen. The best carbonyl planes oxyg calculateden. The throughbest planes the isoquinolinecalculated through and 2-imidazolidinonethe isoquinoline and fragments 2-imidazolidinone fragments form a dihedral angle of 3.49°. The trans configuration of the 2-pirydyl form aand dihedral 2-imidazolidinone-1-yl angle of 3.49◦ fragments. The trans aboutconfiguration a partially double of the C-N 2-pirydyl bond has been and found 2-imidazolidinone-1-yl so far in all fragmentscrystal about structures a partially of N-(2-pyridyl)imidazolidin-2-one double C-N bond has derivatives been found [29–32]. so far It contrasts in all crystal with the structures cis of N-(2-pyridyl)imidazolidin-2-oneconfiguration adopted by this derivatives type of molecule [29–32 in]. Itcoordination contrasts withcompounds the cis configurationwhere they act adoptedas by this typeO,N-chelating of molecule inligands coordination [33]. compoundsMost probably, where theythe act astrans O,N-chelating configuration ligands of [33 ]. Most probably,N-(2-pyridyl)imidazolidin-2-ones the trans configuration of isN -(2-pyridyl)imidazolidin-2-onesstabilized by intramolecular C-H···O isinteraction stabilized with by intramoleculara short C-H OH4···O16 interaction distance with of a2.26 short Å. In H4 crystal,O16 the distance molecules of 2.26 of 3e Å. are In connected crystal, the through molecules a pair of of3e N-H···Oare connected ··· hydrogen bonds (H···O 1.99 Å)··· between 2-imidazolidinone fragments forming centrosymmetric through a pair of N-H O hydrogen bonds (H O 1.99 Å) between 2-imidazolidinone fragments forming dimers. These dimers··· are further connected··· into tapes by much weaker C-H···N interactions (H···N centrosymmetric dimers. These dimers are further connected into tapes by much weaker C-H N Molecules2.60 2019 Å), 24(Figure, x FOR 2). PEER REVIEW 5 of··· 16 interactions (H N 2.60 Å) (Figure2). ···

Figure 1. Molecular structure of 3e. Displacement ellipsoids are shown at the 50% probability level. Figure 1. Molecular structure of 3e. Displacement ellipsoids are shown at the 50% probability level.

Figure 2. Tapes formed via N-H···O and C-H···N interactions in the crystal structure of 3e. Short contacts are indicated with dashed lines.

Absorption measurements were carried out using a Perkin-Elmer Lambda UV/VIS (Evolution 300 UV-vis) spectrophotometer. Spectra were recorded between 190 and 600 nm at 22 ± 2 °C. The fluorescence spectra of selected compounds 3a–f, 5, 7a–d, 8, and 9 were measured under the same conditions. The spectra of the test compounds were recorded in 0.1 M H2SO4 solution. The photophysical properties data of the selected isoquinoline derivatives (3a–f, 5, 7a–d, 8, and 9) are summarized in Table 1. Due to the poor solubility in aqueous solution and organic solvents of the di-substituted isoquinolines 4a–c (minor products), their fluorescent properties were not investigated.

Table 1. Photophysical properties: molar absorptivity (ε), absorption maxima (λmax abs.), emission

maxima (λmax em.), Stokes shift (Δυ) and fluorescence quantum yield (Φfl) of the selected isoquinoline

derivatives in 0.1 M H2SO4*.

ε λmax abs. Δυ Comp. R λmax em. (nm) Φfl (M−1cm−1) (nm) (nm)

3a 5066 368 425 57 0.963

3b 4744 363 417 54 0.559

Molecules 2019, 24, x FOR PEER REVIEW 5 of 16

Molecules 2019, 24, 4070 5 of 16 Figure 1. Molecular structure of 3e. Displacement ellipsoids are shown at the 50% probability level.

FigureFigure 2 2.. TapesTapes formed formed via via N-H···O N-H O and C-H···N C-H N interactions in the crystal structure of 3e3e.. Short Short ··· ··· contactscontacts are are indicated indicated with dashed lines.

AbsorptionAbsorption measurements measurements were were carried carried out out using using a Perkin-Elmer Lambda UV/VIS UV/VIS (Evolution 300 UV-vis) spectrophotometer. Spectra were recorded between 190 and 600 nm at 22 2 C. 300 UV-vis) spectrophotometer. Spectra were recorded between 190 and 600 nm at 22 ± 2 °C.± The◦ fluorescenceThe fluorescence spectra spectra of selected of selected compounds compounds 3a–f, 3a5, –7af,–5d,, 7a8, –andd, 8 ,9 andwere9 measuredwere measured under underthe same the same conditions. The spectra of the test compounds were recorded in 0.1 M H SO solution. conditions. The spectra of the test compounds were recorded in 0.1 M H2SO4 2solution.4 The photophysicalThe photophysical properties properties data data of th ofe theselected selected isoquinoline isoquinoline derivatives derivatives (3a (3a–f–, f5,,5 7a, 7a–d–,d 8, ,8 ,and and 99)) are are summarizedsummarized in in Table Table 11.. DueDue toto thethe poorpoor solubilitysolubility inin aqueousaqueous solutionsolution andand organicorganic solventssolvents ofof thethe di-substituteddi-substituted isoquinolinesisoquinolines4a –4ac –(minorc (minor products), products), their fluorescenttheir fluor propertiesescent properties were not investigated.were not investigated.The photophysical properties may be strongly affected by solvent properties. In protic hydrogen-bonding solvents such as water, quantum yields are higher compared to hydrocarbon solvents.Table In 1. casePhotophysical of heteroaromatic properties: compounds, molar absorptivity e.g., quinolines (ε), absorption or isoquinolines, maxima (λmax the abs. hydrogen), emission bond 1 betweenmaxima the lone(λmax em. pair), Stokes electrons shift on (Δ theυ) and nitrogen fluorescence atom andquantum water yield stabilizes (Φfl) of the the (selectedπ,π*) state, isoquinoline destabilizing 1 the (n,derivativesπ*) state in [34 0.1]. M This H2SO increases4*. the energy gap, reducing the vibronic interaction between the states and results in enhance of fluorescence. The solvent used may have a significant effect on the determined absorption maxima (λmax) and the molar absorption coefficient (εmax). The most preferred solvent is water, which occurs under physiological conditions and has a permeability limit of 200 nm. In addition, the high polarity of water can cause bathochromicε λ shiftsmax abs. of the bands π π* andΔ hypsochromicυ shifts Comp. R λmax em. (nm)→ Φfl of bands n π*, associated with(M groups−1cm− capable1) of(nm) binding a free electron pair(nm) with hydrogen bonds. → Thus, compounds 3a–e, 5, 8, and 9 were studied in acidic aqueous solution. In the case of compounds 3f3aand 7a–d, chloroform was chosen.5066 368 425 57 0.963 The emission maxima of isoquinoline derivatives 3a–f, 5, 7a, 7b, and 7d range from 328 to 391 nm (near-ultraviolet region). By contrast, strong electron-withdrawing properties of the NO2 group ensures that 1-(isoquinolin-3-yl)-3-(4-nitrophenyl)imidazolidin-2-one (7c) has no intrinsic emission 3b 4744 363 417 54 0.559 (absmax = 350 nm). Fluorescence quenching or decreasing intensity may be observed in the case of nitro compounds [35,36]. Compounds 8 and 9 display the same absorption maximum at 406 nm and have favorably long emission wavelengths (494 and 495 nm). A disadvantage of the compounds 8 and 9 is their low quantum yields: 0.223 10 13 and 0.053, respectively. Therefore, in the case of 9, a very weak emission · − spectrum was observed. Experiments with isoquinoline derivatives bearing a 4, 5 or 6-membered lactam ring 3a–d provided additional evidence that the absorption and emission spectra are dependent upon their chemical structure. The highest quantum yield value (0.963) was observed for 1-(isoquinolin-3-yl)azetidin-2-one (3a), which could be due to the greater structural rigidity. A four-membered ring coupled to the isoquinoline with restricted rotation leads to stabilization of the structure (Figure3). Molecules 2019, 24, x FOR PEER REVIEW 5 of 16

Molecules 2019, 24, x FOR PEER REVIEW 5 of 16 Molecules 2019, 24, x FOR PEER REVIEW 5 of 16

Figure 1. Molecular structure of 3e. Displacement ellipsoids are shown at the 50% probability level.

Figure 2. Tapes formed via N-H···O and C-H···N interactions in the crystal structure of 3e. Short contacts are indicated with dashed lines.

Figure 2. Tapes formed via N-H···O and C-H···N interactions in the crystal structure of 3e. Short Figure 2. Tapes formed via N-H···O and C-H···N interactions in the crystal structure of 3e. Short contacts are indicated with dashed lines. Absorptioncontacts measurements are indicated with were dashed carried lines. out using a Perkin-Elmer Lambda UV/VIS (Evolution 300 UV-vis) spectrophotometer. Spectra were recorded between 190 and 600 nm at 22 ± 2 °C. The Absorption measurements were carried out using a Perkin-Elmer Lambda UV/VIS (Evolution fluorescence spectraAbsorption of selected measurements compounds were carried 3a –outf, 5using, 7a –ad Perkin, 8, and-Elmer 9 wereLambda measured UV/VIS (Evolution under the same 300 UV-vis) spectrophotometer. Spectra were recorded between 190 and 600 nm at 22 ± 2 °C. The conditions.fluorescence The spectra spectra of of the selected test compounds compounds 3a–f , 5 were, 7a–d , recorded8, and 9 were in measured 0.1 M under H2SO the4 solution.same The conditions. The spectra of the test compounds were recorded in 0.1 M H2SO4 solution. The photophysicalconditions. properties The spectra data of of the testselected compounds isoquinoline were recorded derivatives in 0.1 M(3a H–2SOf, 45 ,solution. 7a–d, 8 The, and 9) are summarizedphotophysical in Table 1. properties Due to datathe ofpoor the selectedsolubility isoquinoline in aqueous derivatives solution (3a– fand, 5, 7a organic–d, 8, and solvents 9) are of the summarized in Table 1. Due to the poor solubility in aqueous solution and organic solvents of the di-substitutedsummarized isoquinolines in Table 1. Due4a– cto the(minor poor solubility products) in aqueous, their solution fluorescent and organic properties solvents of thewere not di-substituted isoquinolines 4a–c (minor products), their fluorescent properties were not Moleculesinvestigated.2019investigated., 24 , 4070 6 of 16

Table 1. Photophysical properties: molar absorptivity (ε), absorption maxima (λmax abs.), emission Table 1. PhotophysicalTable 1. Photophysical properties: properties: molar molar absorptivity absorptivity ( (ε)ε), , absorption absorption maxima maxima (λmax abs.(λ), max emission abs.), emission maxima (λmax em.), Stokes shift (Δυ) and fluorescence quantum yield (Φfl) of the selected isoquinoline maxima (λmax em.), Stokes shift (Δυ) and fluorescence quantum yield (Φfl) of the selected isoquinoline Tablemaxima 1. (Photophysicalλmax em.), Stokes properties: shift (Δυ) and molar fluorescence absorptivity quantum (ε), absorption yield (Φfl maxima) of the selected (λ isoquinoline), emission derivatives in 0.1 M H2SO4*. max abs. derivatives in 0.1 M H2SO4*. maximaderivatives (λmax in em.0.1 ),M Stokes H2SO4 shift*. (∆υ) and ﬂuorescence quantum yield (Φﬂ) of the selected isoquinoline derivatives in 0.1 M H2SO4*.

ε λmax abs. Δυ Comp. R ε λmax abs. λmax em. (nm) Δυ Φfl Comp.Molecules 2019, 24, x FORR PEER REVIEW (M−1cm−1) (nm) λmax em. (nm) (nm) Φ6 flof 16 Molecules 2019, 24, x FOR PEER REVIEW (M−1cm−11 ) 1 (nm) (nm) 6 of 16 Comp.Molecules 2019, 24, x FOR R PEER REVIEW ε (M− cm− ) λmax abs. (nm) λmax em. (nm) ∆υ (nm) 6 of 16Φ ﬂ Molecules 2019, 24, x FOR PEER REVIEWε λmax abs. Δυ 6 of 16 Comp. R λmax em. (nm) Φfl 3a (M−1cm5066−1) (nm)368 425 57 (nm) 0.963 3aMolecules3a 2019, 24, x FOR PEER REVIEW 50665066 368 368425 42557 570.9636 of 0.96316 3c 2955 356 417 61 0.954 Molecules3c 2019, 24, x FOR PEER REVIEW 2955 356 417 61 0.956 of4 16 Molecules3c 2019, 24, x FOR PEER REVIEW 2955 356 417 61 0.956 of4 16 Molecules3c 2019, 24, x FOR PEER REVIEW 2955 356 417 61 0.956 of4 16 3a Molecules 2019, 24, x FOR PEER REVIEW5066 368 425 57 6 of 16 0.963 Molecules 2019, 24, x FOR PEER REVIEW 6 of 16 Molecules3b3b 2019, 24, x FOR PEER REVIEW 47444744 363 363417 41754 540.5596 of 0.55916 3c 2955 356 417 61 0.954

3c 2955 356 417 61 0.954 3d3c 25412955 340356 416417 7661 0.3890.954 3d3c 25412955 340356 416417 7661 0.3890.954 3c3d 29552541 356340 417416 6176 0.950.3894 3c 2955 356 417 61 0.954 3b 3c 4744 2955363 356417 417 6154 0.9540.559

3d 2541 340 416 76 0.389

3e 5083 377 436 59 0.639 3d3e3d 254150832541 340377340 416436416 765976 0.3890.6390.389 3e3d3e 508325415083 377340377 436416436 597659 0.6390.3890.639 3d 2541 340 416 76 0.389 3d 2541 340 416 76 0.389 3d3d 25412541 340 340416 41676 760.389 0.389 3e 5083 377 436 59 0.639

3f* 2032 328 383 55 0.101 3f*3e3e 508320325083 377328377 436383436 595559 0.6390.1010.639 3f*3e3f* 203250832032 328377328 383436383 555955 0.1010.6390.101 3e3e 50835083 377 377436 43659 590.639 0.639 3e 5083 377 436 59 0.639

3f* 2032 328 383 55 0.101 5 5271 380 448 68 0.479 3f*3f*5 203252712032 328380328 383448383 556855 0.1010.4790.101 3f*3f*55 5271203252712032 380328380 328448383448 383685568 550.4790.1010.479 0.101 3f* 2032 328 383 55 0.101 3f* 2032 328 383 55 0.101 3f* 2032 328 383 55 0.101

5 5271 380 448 68 0.479 7a* 34,537 302 391 89 0.251 7a*5 345271,537 380302 448391 6889 0.4790.251 7a*57a*5 34345271,537,5375271 302380302 380391448391 448896889 680.2510.4790.251 0.479 5 5271 380 448 68 0.479 5 5271 380 448 68 0.479 5 5271 380 448 68 0.479

7a* 34,537 302 391 89 0.251

7a*7a*7a* 3434,,53753734,537 302302 302391391 3918989 890.2510.251 0.251 7b*7a* 342251,537 344302 391 4789 0.4430.251 7b*7a*7b* 3422512251,537 344302344 391391 478947 0.4430.2510.443 7a* 34,,537 302 391 89 0.251

7b* 2251 344 391 47 0.443 7b* 2251 344 391 47 0.443

7b* 2251 344 391 47 0.443 7b* 2251 344 391 47 0.443 7b*7c* 112251,072 350344 391nd nd47 0.443nd 7b*7c*7c* 11112251,072,072 350344350 391ndnd nd47nd 0.443ndnd 7c* 11,072 350 nd nd nd

7c* 11,072 350 nd nd nd

7d*7c* 1115,072581 350304 385nd nd81 0.570nd 7d*7c* 1511,,581072 304350 385nd 81nd 0.570nd 7d*7d*7c*7d* 151115,,581,07215,581581 304350304 304385385nd 38581nd81 810.5700.570nd 0.570 7c* 11,072 350 nd nd nd 7c* 11,,072 350 nd nd nd

7d* 15,581 304 385 81 0.570 8 3826 406 495 89 2.23 10−14 8 3826 406 495 89 2.23·10−14 14 7d*88 153826,5813826 406304 406495385 4958981 89 2.230.570·102.23−1 4 10− 7d*8 153826,,581 304406 385495 8189 2.230.570·10 −1·4 7d* 15,581 304 385 81 0.570 7d* 15,,581 304 385 81 0.570 −14 8 3826 406 495 89 2.23·10 99 37053705 406 406494 49488 880.053 0.053 89 38263705 406 495494 8988 2.230.05310−1 4 98 37053826 406406 494495 8889 2.230.053·10 −14 89 38263705 406406 495494 8988 2.230.053·10−1 4 8 3826 406 495 89 2.23 10−14 · −14 8 3826 406 495 89 2.23·10−14 I-3-A**I-3-8A** 3826nd nd 363406 363431495 4316889 682.230.28·10 0.28 IQS***-3-A**9 3705nd (exc.363 406at 350) 431nd494 68nd88 0.5770.280.053 QS***QS***I-3-A** ndnd nd (exc. 363at(exc. 350) at 350) nd431 ndnd68 nd 0.5770.28 0.577 QS***QS***9 *compounds were dissolved in3705 ndnd chloroform. (exc.(exc. nd406 at at 350)- 350) not determined494ndnd . ** 3-aminoisoquinolinend88nd 0.5770.0530.577 9 *compounds were dissolved in3705 chloroform. nd406 - not determined494 . ** 3-aminoisoquinoline88 0.053 9 *compounds were dissolved in3705 chloroform. nd406 - not determined494 . ** 3-aminoisoquinoline88 0.053 I-39-A** (isoquinolin*compounds -3 -amine) were dissolveddissolved in in3705 acetonitrilend chloroform. [14 nd406].363 *** - quininenot determined sulfate494431 in. 0.1 ** M 3- aminoisoquinoline H88682SO 4 (used as0.053 0.28 a * compounds9 (isoquinolin were dissolved-3-amine) in chloroform.dissolved in3705 acetonitrilend - not determined. [14406]. *** quinine ** 3-aminoisoquinoline sulfate494 in 0.1 M H882SO (isoquinolin-3-amine)4 (used as0.053 a 9 (isoquinolin -3-amine) dissolved in3705 acetonitrile [14406]. *** quinine sulfate494 in 0.1 M H882SO 4 (used as0.053 a dissolvedQS*** in acetonitrilestandard)(isoquinolin . - [314-amine)]. *** quinine dissolved sulfate in nd acetonitrile in 0.1 M(exc. [ H14].SO at *** 350) (used quinine as sulfate and standard). in 0.1 M Hnd2SO 4 (used as0.577 a I-3-A**standard) . nd 3632 4 431 68 0.28 II--3--A**standard) . nd 363 431 68 0.28 IQS***-3-A**standard)*compounds . were dissolved innd chloroform. (exc. 363nd at 350) - not determined431nd . ** 3-aminoisoquinolinend68 0.5770.28 IQS***-3-A** ndnd (exc.(exc.363 atat 350) 350) 431nd 68nd 0.5770.28 I-3-A***compoundsThe(isoquinolin photophysical -3 were-amine) dissolved propertiesdissolved in in nd may chloroform.acetonitrile be strongly [14nd363]. ***- not affected quinine determined sulfate431 by solvent .in ** 0.1 3 M-aminoisoquinoline properties. 68 H2 SO4 (used In as 0.28 protic a QS***The*compounds photophysical were dissolved properties in nd may chloroform. be (exc. strongly nd at 350)- not affected determined nd by solvent. ** 3- properties.aminoisoquinolinend In 0.577 protic QS***hydrogen*compoundsThestandard) -bonding photophysical. were solvents dissolved properties such inas nd water, chloroform.may be quantum (exc. strongly nd at 350)- yields not affected determined are nd higher by solvent. compared ** 3 -aminoisoquinoline properties.nd to hydrocarbon In0.577 protic hydrogen(isoquinolin*compounds-bonding-3 - wereamine) solvents dissolved dissolved such inas acetonitrile water, chloroform. quantum [ 14nd]. ***- yields quininenot determined are sulfate higher in. 0.1compared ** M 3- aminoisoquinoline H2SO to4 (used hydrocarbon as a hydrogen*compounds(isoquinolin-bonding- 3- wereamine) solvents dissolved dissolved such inas in acetonitrilewater, chloroform. quantum [ 14nd]. ***- yields not quinine determined are sulfate higher in. compared 0.1** 3M-aminoisoquinoline H2SO to4 (used hydrocarbon as a hydrogenstandard)(isoquinolin*compounds-bonding. - 3- wereamine) solvents dissolved dissolved such in as acetonitrile chloroform. water, quantum [ 14nd]. ***- yields quininenot determined are sulfate higher in. 0.1 ** compared M 3-aminoisoquinoline H2SO 4to (used hydrocarbon as a (isoquinolinstandard). -3-amine) dissolved in acetonitrile [14]. *** quinine sulfate in 0.1 M H2SO4 (used as a (isoquinolinstandard)The photophysical. -3-amine) dissolved properties in acetonitrile may be strongly[14]. *** quinine affected sulfate by in solvent 0.1 M properties.H2SO4 (used Inas a protic standard)(isoquinolin. -3-amine) dissolved in acetonitrile [14]. *** quinine sulfate in 0.1 M H2SO4 (used as a

hydrogenThestandard) photophysical-bonding.. solvents properties such as may water, be quantum strongly yields affected are by higher solvent compared properties. to hydrocarbon In protic The photophysical properties may be strongly affected by solvent properties. In protic hydrogenThe - photophysicalbonding solvents properties such as maywater, be quantum strongly yields affected are higherby solvent compared properties. to hydrocarbon In protic hydrogen The -- photophysicalbonding solvents properties such as may water, be quantum strongly yields affected are higherby solvent compared properties. to hydrocarbon In protic hydrogenThe - photophysicalbonding solvents properties such as may water, be quantum strongly yields affected are higherby solvent compared properties. to hydrocarbon In protic hydrogen-bonding solvents such as water, quantum yields are higher compared to hydrocarbon hydrogen -bonding solvents such as water, quantum yields are higher compared to hydrocarbon

Molecules 2019, 24, x FOR PEER REVIEW 7 of 16 solvents. In case of heteroaromatic compounds, e.g., quinolines or isoquinolines, the hydrogen bond between the lone pair electrons on the nitrogen atom and water stabilizes the 1(π,π*) state, destabilizing the 1(n,π*) state [34]. This increases the energy gap, reducing the vibronic interaction between the states and results in enhance of fluorescence. The solvent used may have a significant effect on the determined absorption maxima (λmax) and the molar absorption coefficient (εmax). The most preferred solvent is water, which occurs under physiological conditions and has a permeability limit of 200 nm. In addition, the high polarity of water can cause bathochromic shifts of the bands π → π* and hypsochromic shifts of bands n → π*, associated with groups capable of binding a free electron pair with hydrogen bonds. Thus, compounds 3a–e, 5, 8, and 9 were studied in acidic aqueous solution. In the case of compounds 3f and 7a–d, chloroform was chosen. The emission maxima of isoquinoline derivatives 3a–f, 5, 7a, 7b, and 7d range from 328 to 391 nm (near-ultraviolet region). By contrast, strong electron-withdrawing properties of the NO2 group ensures that 1-(isoquinolin-3-yl)-3-(4-nitrophenyl)imidazolidin-2-one (7c) has no intrinsic emission (absmax = 350 nm). Fluorescence quenching or decreasing intensity may be observed in the case of nitro compounds [35,36]. Compounds 8 and 9 display the same absorption maximum at 406 nm and have favorably long emission wavelengths (494 and 495 nm). A disadvantage of the compounds 8 and 9 is their low quantum yields: 0.223.10−13 and 0.053, respectively. Therefore, in the case of 9, a very weak emission spectrum was observed. Experiments with isoquinoline derivatives bearing a 4, 5 or 6-membered lactam ring 3a–d provided additional evidence that the absorption and emission spectra are dependent upon their chemical structure. The highest quantum yield value (0.963) was observed for 1-(isoquinolin-3-yl)azetidin-2-one (3a), which could be due to the greater structural rigidity. A Moleculesfour-membered2019, 24, 4070 ring coupled to the isoquinoline with restricted rotation leads to stabilization of7 of the 16 structure (Figure 3).

Figure 3.3. Absorption and ﬂuorescencefluorescence spectra ofof 1-(isoquinolin-3-yl)azetidin-2-one1-(isoquinolin-3-yl)azetidin-2-one ((3a3a).).

TableTable1 1 shows shows thatthat thethe fluorescencefluorescence intensity intensity decrea decreasesses with with increasing increasing heterocyclic heterocyclic ring ring size. size. In Incontrast contrast to tothe the 3a3a withwith the the ββ-lactam-lactam ring, ring, compound compound 3d3d withwith a a 6-membered 6-membered ring displays a lowerlower −11 −11 quantumquantum yieldyield (0.389)(0.389) andand molarmolar extinctionextinction coecoefficientfficient (2541(2541 MM− cm−).). CompoundsCompounds 3a-f displaydisplay smallsmall StokesStokes shiftsshifts rangingranging fromfrom 5454 toto 7676 nm.nm. Figure4 4 shows shows the the fluorescencefluorescence ofof compoundscompounds 3a3a,, 3b3b,, 3d3d,, andand 3e3e inin 0.10.1 MM H H2SO2SO44.. In this groupgroup thethe highesthighest molarmolar −11 −1 extinctionextinction coecoefficientfficient (5083(5083 M M− cmcm− )) displays 1-(isoquinolin-3-yl)imidazolidin-2-one (3e), whereaswhereas −1 1 −1 1 thethe lowest is observed observed for for 1 1HH-benzimidazol-2(3-benzimidazol-2(3HH)-one)-one derivative derivative 3f3f (2032(2032 M Mcm− cm). −Compounds). Compounds 3a-c 3a-cand and3e can3e canbe excited be excited at 356, at 356, 363, 363, 368, 368, and and 377 377 nm. nm. Figure Figure 5 showsshows absorptionabsorption andand fluorescencefluorescence MoleculesspectraMoleculesspectra of20192019of 1-(isoquinolin-3-yl)imidazolidin-2-one ,1-(isoquinolin-3-yl)imidazolidin-2-one, 2424,, xx FORFOR PEERPEER REVIEWREVIEW (3e ).(3e In). contrastIn contrast to compound to compound3e, its 3eN-methyl, its N-methyl analog88 ofof 1616 5analogobtained 5 obtained from 3e infrom reaction 3e in with reaction methyl with iodide methyl has iodide lower fluorescencehas lower fluorescence quantum yield quantum (0.479). yield The (0.479).(0.479). TheThe absorptionabsorption andand emissionemission maximamaxima ofof thethe NN-methyl-methyl derivativederivative 55 areare red-shiftedred-shifted (380(380 nmnm absorption and emission maxima of the N-methyl derivative 5 are red-shifted (380 nm and 448 nm). andand 448448 nm).nm).

FigureFigure 4.44.. Photograph PhotographPhotograph of of ﬂuorescenceof fluorescencefluorescence of compounds ofof compoundscompounds3a, 3b ,3a3a3d,, ,3b and3b,, 3d3e3d,in, andand 0.1 M3e3e H 2ininSO 0.10.14 at M aM concentration HH22SOSO44 atat aa 4 −4 concentrationofconcentration 10− M under ofof 10 UV10−4 (365MM underunder nm) light.UVUV (365(365 nm)nm) light.light.

FigureFigure 5 5.5.. AbsorptionAbsorption andand fluorescencefluorescence ﬂuorescence spectra spectra of of 1- 1-(isoquinolin-3-yl)imidazolidin-2-one1-(isoquinolin-3-yl)imidazolidin-2-one(isoquinolin-3-yl)imidazolidin-2-one ( (3e3e).).

DueDue toto thethe lacklack ofof solubilitysolubility ofof 1-(isoquinolin-3-yl)-3-(hetero)aryl-2-ones1-(isoquinolin-3-yl)-3-(hetero)aryl-2-ones 7a7a--dd inin waterwater andand aa 0.10.1 molarmolar solutionsolution ofof sulfuricsulfuric acid,acid, thethe spectraspectra werewere recordedrecorded inin chloroformchloroform (permeability(permeability limit:limit: 250250 nm).nm). CompoundsCompounds 7a7a--dd areare characterizedcharacterized byby thethe absorptionabsorption ofof electromagneticelectromagnetic radiationradiation inin thethe near-ultravioletnear-ultraviolet range.range. TheThe observedobserved absorptionabsorption maximamaxima areare foundfound atat thethe followingfollowing wavelengths:wavelengths: 302302 nmnm ((7a7a),), 344344 nmnm ((7b7b),), 350350 nmnm ((7c7c),), andand 304304 nmnm ((7d7d).). TheThe heteroaromaticheteroaromatic derivativederivative 7d7d withwith thethe pyridinepyridine ringring hashas anan electronelectron spectrumspectrum veryvery closeclose toto itsits analoganalog 7a7a (absorption(absorption maximamaxima 304304 andand 302302 nm).nm). TheThe presencepresence ofof thethe substituentsubstituent atat thethe C-4C-4 posipositiontion ofof thethe phenylphenyl ring,ring, bothboth anan electronelectron donordonor (OCH(OCH33)) andand anan electronelectron acceptoracceptor (NO(NO22),), causescauses aa bathochromicbathochromic shiftshift ofof thethe absorptionabsorption bandband ((ππ →→ ππ*)*) byby thethe followingfollowing values:values: 4242 nmnm ((7b7b)) andand 4848 nmnm ((7c7c).). TheThe compoundscompounds 7a7a,, 7b7b,, andand 7d7d emitemit violetviolet lightlight inin solution.solution. TheThe attemptattempt toto registerregister thethe ememissionission spectrumspectrum ofof thethe 4-nitrophenyl4-nitrophenyl derivativederivative 7c7c failed.failed. TheThe presencepresence inin thethe structurestructure ofof thethe nitronitro groupgroup associatedassociated withwith thethe aromaticaromatic ringring causescauses fluorescencefluorescence quenching.quenching. TheThe determineddetermined emissionemission maximamaxima ofof thethe compoundscompounds 7a7a,, 7b7b,, andand 7d7d areare respectively:respectively: 391391 nmnm ((7a7a andand 7b7b)) andand 385385 nmnm ((7d7d).). InIn comparisoncomparison withwith ththee unsubstitutedunsubstituted compoundcompound 7a7a,, thethe presencepresence ofof thethe methoxymethoxy substituentsubstituent atat thethe C-4C-4 positionposition ofof thethe phenylphenyl ringring ((7b7b)) doesdoes notnot changechange thethe emissionemission properties.properties. CompoundCompound 7a7a displaysdisplays thethe strongeststrongest absorptionabsorption ((λλmaxmax == 302302 nm)nm) andand −1 −1 thethe molarmolar absorptionabsorption coefficientcoefficient ((εεmaxmax)) waswas 34,53734,537 MM−1cmcm−1.. LowerLower valuesvalues ofof thethe molarmolar absorptionabsorption coefficientcoefficient werewere determineddetermined forfor compoundscompounds 7c7c andand 7d7d:: 11,07211,072 MM−−11cmcm−−11 andand 15,58115,581 MM−−11cmcm−−11 −1 −1 respectively.respectively. TheThe lowestlowest value,value, εεmaxmax,, ofof 22512251 MM−1cmcm−1 waswas characterizedcharacterized byby thethe compoundcompound 7b7b withwith aa methoxymethoxy substituent.substituent. HigherHigher valuesvalues ofof ththee StokesStokes shiftshift werewere recordedrecorded forfor compoundscompounds 7a7a ((ΔυΔυ == 8989 nm)nm) andand 7d7d ((ΔυΔυ == 8181 nm).nm).

3.3. ExperimentalExperimental DetailsDetails Materials.Materials. QuinineQuinine hemisulfatehemisulfate saltsalt monohydratemonohydrate ofof ≥≥98.0%98.0% puritypurity suitablesuitable forfor fluorescencefluorescence waswas obtainedobtained fromfrom Sigma-Aldrich.Sigma-Aldrich. AllAll ofof thethe solventssolvents andand reagentsreagents usedused inin thisthis studystudy werewere ofof analyticalanalytical grade.grade.

Molecules 2019, 24, 4070 8 of 16

Due to the lack of solubility of 1-(isoquinolin-3-yl)-3-(hetero)aryl-2-ones 7a-d in water and a 0.1 molar solution of sulfuric acid, the spectra were recorded in chloroform (permeability limit: 250 nm). Compounds 7a-d are characterized by the absorption of electromagnetic radiation in the near-ultraviolet range. The observed absorption maxima are found at the following wavelengths: 302 nm (7a), 344 nm (7b), 350 nm (7c), and 304 nm (7d). The heteroaromatic derivative 7d with the pyridine ring has an electron spectrum very close to its analog 7a (absorption maxima 304 and 302 nm). The presence of the substituent at the C-4 position of the phenyl ring, both an electron donor (OCH3) and an electron acceptor (NO ), causes a bathochromic shift of the absorption band (π π*) by the following values: 2 → 42 nm (7b) and 48 nm (7c). The compounds 7a, 7b, and 7d emit violet light in solution. The attempt to register the emission spectrum of the 4-nitrophenyl derivative 7c failed. The presence in the structure of the nitro group associated with the aromatic ring causes fluorescence quenching. The determined emission maxima of the compounds 7a, 7b, and 7d are respectively: 391 nm (7a and 7b) and 385 nm (7d). In comparison with the unsubstituted compound 7a, the presence of the methoxy substituent at the C-4 position of the phenyl ring (7b) does not change the emission properties. Compound 7a displays the strongest absorption (λmax = 302 nm) and the molar absorption coefficient (εmax) was 1 1 34,537 M− cm− . Lower values of the molar absorption coefficient were determined for compounds 7c 1 1 1 1 1 1 and 7d: 11,072 M− cm− and 15,581 M− cm− respectively. The lowest value, εmax, of 2251 M− cm− was characterized by the compound 7b with a methoxy substituent. Higher values of the Stokes shift were recorded for compounds 7a (∆υ = 89 nm) and 7d (∆υ = 81 nm).

3. Experimental Details Materials. Quinine hemisulfate salt monohydrate of 98.0% purity suitable for fluorescence ≥ was obtained from Sigma-Aldrich. All of the solvents and reagents used in this study were of analytical grade. Methods. Freshly prepared acidic medium 0.1 M H2SO4 for optical measurements, as well as freshly prepared solutions of compounds, were used. Fluorescence quantum yields were determined in reference to the solution of quinine sulfate in 0.1 M H2SO4 (Φf = 0.577, at the wavelength of excitation 350 nm) [37]. The melting points were determined using a Boetius apparatus (VEB Analytik Dresden) and are uncorrected. The infrared spectra were obtained using a Nicolet 380 FTIR spectrophotometer in potassium bromide or in the liquid film. Magnetic resonance spectra (NMR) were recorded with a Varian Gemini 200 BB (1H 200 MHz) spectrometer, Varian Unity Inova 500 (1H 500 MHz) or Varian Mercury-VX 300 (1H 300 MHz) spectrometer. Chemical shifts (δ) are reported in ppm relative to residual solvent signals. Coupling constants (J) are given in Hz. The mass spectra were recorded on a Shimadzu LCMS 2010 instrument in positive ion mode with an electrospray ionization source (ESI) using a mixture of methanol and acetonitrile containing 0.1% of acetic acid (1:1). The absorption spectra were obtained using a Perkin-Elmer Lambda UV/VIS (Evolution 300 UV-vis) spectrophotometer. The fluorescence spectra were recorded on a Hitachi F-7000 (Scinco FS-2) fluorescence spectrometer. Compounds were purified by preparative thin-layer chromatography using a Harrison Research Inc. USA chromatotron. Plates were coated with silica gel containing 30% gypsum (Merck Silica Gel PF254). Dichloromethane-ethyl acetate or diethyl ether mixtures as mobile phases were applied. Thin-layer chromatography was performed on silica gel plates with fluorescence detection (Merck Silica Gel 254). After drying, spots were detected under UV light at 254 nm or 365 nm.

A representative procedure for the reaction of 3-bromoisoquinoline with β, γ, δ-lactams, imidazolidin-2-one, 2-hydroxybenzimidazole or 5-methoxy-1H-benzimidazol-2(3H)-one (3a–h, 4a–c)

To a stirring solution of 3-bromoisoquinoline (0.104 g, 0.5 mmol) in n-butanol (2–3 cm3) was added the appropriate lactam (β, γ, δ), imidazolidin-2-one, 2-hydroxybenzimidazole or 5-methoxy-1H-benzimidazol-2(3H)-one (0.5–2.5 mmol), potassium carbonate (0.207 g, 1.5 mmol), Molecules 2019, 24, 4070 9 of 16 copper(I) iodide (0.01g, 0.05 mmol), and N,N-dimethylethylenediamine (DMEDA) (0.013 g, 0.15 mmol). For the synthesis of compound 3a, anhydrous 1,4-dioxane was used at 90 ◦C. A mixture was heated in an oil bath at 90–100 ◦C for 3–80 h. The progress of the reaction was controlled by TLC. The mixture was then evaporated under reduced pressure and the residue was extracted four times with 10 cm3 portions of chloroform, dried over anhydrous MgSO4 and ﬁltered. The solvent was removed in vacuo and the semi-crystalline residue was puriﬁed on silica gel by preparative thin-layer chromatography (chromatotron). Thus, the chemical yield of the isolated product was determined.

1-(Isoquinolin-3-yl)azetidin-2-one (3a)

Starting from 0.036 g (0.5 mmol) azetidin-2-one; yield 3a 0.06 g (61%); reaction time 48 h; eluent: 1 dichloromethane followed by diethyl ether; m.p. 142–146 ◦C; νmax (KBr, cm− ): 3085, 3044, 3003, 2983, 2914, 1739, 1630, 1590, 1466, 1390, 1241, 1138, 849, 752; δH (200 MHz, CDCl3): 3.16 (t, 2H, CH2); 3.91 (t, 2H, CH2); 7.46 (t, 1H, isoquin.); 7.64 (t, 1H, isoquin.); 7.78 (d, J = 8.3 Hz, 1H, isoquin.); 7.89 (d, J = 7.9 Hz, 1H, isoquin.); 8.05 (s, 1H, isoquin.); 9.01 (s, 1H, isoquin.); δC (50 MHz, CDCl3): 36.24, 38.30, 107.47, 125.97, 126.52, 126.67, 127.88, 131.16, 137.82, 145.43, 151.72, 165.30; m/z (ESI): 199 [M+H]+. Anal. Calcd for C12H10N2O (198.22): C, 72.71; H, 5.08; N, 14.13. Found: C, 72.56; H, 5.23; N, 14.01.

1-(Isoquinolin-3-yl)pyrrolidin-2-one (3b)

Starting from 0.128 g (1.5 mmol) pyrrolidin-2-one; yield 3b 0.06 g (57%); reaction time 65 h; eluent: 1 dichloromethane:ethyl acetate, (19:1 and 9:1, v/v); m.p. 100–105 ◦C; νmax (KBr, cm− ): 3098, 3063, 3037, 2999, 2967, 2905, 1690, 1624, 1582, 1489, 1448, 1397, 1356, 1292, 1238, 881, 755; δH (500 MHz, DMSO-d6): 2.08 (qui, 2H, CH2); 2.61 (t, 2H, CH2); 4.11 (t, 2H, CH2); 7.55 (t, 1H, isoquin.); 7.71 (t, 1H, isoquin.); 7.93 (d, J = 8.2 Hz, 1H, isoquin.); 8.06 (d, J = 8.2 Hz, 1H, isoquin.); 8.64 (s, 1H, isoquin.); 9.19 (s, 1H, isoquin.); + m/z (ESI): 213 [M+H] . Anal. Calcd for C13H12N2O (212.25): C, 73.56; H, 5.70; N, 13.20. Found: C, 73.26; H, 5.98; N, 12.86.

1-(Isoquinolin-3-yl)-3-methylpyrrolidin-2-one (3c)

Starting from 0.099 g (1 mmol) 3-methylpyrrolidin-2-one; yield 3c 0.09 g (80%) as an oil; reaction 1 time 5 h; eluent: dichloromethane:ethyl acetate, (1:1, v/v); νmax (liquid ﬁlm, cm− ): 3058, 2973, 2926, 1698, 1627, 1584, 1448, 1392, 1236, 1207, 1139, 753; δH (500 MHz, CDCl3): 1.36 (d, J = 6.35 Hz, 3H, CH3); 1.79–1.85 (m, 1H, CH2); 2.37–2.44 (m, 1H, CH2); 2.60–2.67 (m, 1H, CH2); 2.77–2.84 (m, 1H, CH2); 5.04–5.08 (m, 1H, CH); 7.53 (t, 1H, isoquin.); 7.68 (t, 1H, isoquin.); 7.86 (d, J = 8.3 Hz, 1H, isoquin.); 7.94 (d, J = 8.3 Hz, 1H, isoquin.); 8.55 (s, 1H, isoquin.); 9.12 (s, 1H, isoquin.); δC (125 MHz, DMSO-d6): 20.55, 26.08, 32.35, 54.78, 112.14, 126.50 (two overlapping signals), 127.11, 127.58, 130.88, 137.87, 146.00, + 150.70, 174.67; m/z (ESI): 227 [M+H] . Anal. Calcd for C14H14N2O (226.27): C, 74.31; H, 6.24; N, 12.38. Found: C, 74.06; H, 6.38; N, 12.20.

1-(Isoquinolin-3-yl)piperidin-2-one (3d)

Starting from 0.149 g (1.5 mmol) piperidin-2-one; yield 3d 0.04 g (35%); reaction time 5 h; eluent: 1 dichloromethane:ethyl acetate, (9:1, v/v) followed by diethyl ether; m.p. 81–83 ◦C; νmax (KBr, cm− ): 3060, 2938, 2873, 1655, 1624, 1577, 1481, 1446, 1409, 1352, 1300, 763; δH (500 MHz, DMSO-d6): 1.85–1.93 (m, 4H, 2 CH ); 2.48–2.50 (m, 2H, CH ), 3.90 (t, 2H, CH ); 7.62 (t, 1H, isoquin.); 7.75 (t, 1H, isoquin.); × 2 2 2 7.94 (d, J = 8.3 Hz, 1H, isoquin.); 8.01 (s, 1H, isoquin.); 8.11 (d, J = 8.3 Hz, 1H, isoquin.); 9.24 (s, 1H, + isoquin.); m/z (ESI): 227 [M+H] . Anal. Calcd for C14H14N2O (226.27): C, 74.31; H, 6.24; N, 12.38. Found: C, 74.48; H, 6.30; N, 12.51.

1-(Isoquinolin-3-yl)imidazolidin-2-one (3e) Molecules 2019, 24, 4070 10 of 16

Starting from 0.215 g (2.5 mmol) imidazolidin-2-one; yield 3e 0.038 g (36%); reaction time 3 h; 1 eluent: dichloromethane:ethyl acetate, (8:2, v/v); m.p. 233–236◦C; νmax (KBr, cm− ): 3201, 3111, 3053, 2996, 2965, 2902, 1717, 1625, 1583, 1488, 1454, 1415, 1365, 1268, 877, 750; δH (500 MHz, DMSO-d6): 3.43 (t, 2H, CH2); 4.11 (t, 2H, CH2); 7.20 (s, 1H, NH); 7.44 (t, 1H, isoquin.); 7.64 (t, 1H, isoquin.); 7.83 (d, J = 8.2 Hz, 1H, isoquin.); 7.98 (d, J = 8.2 Hz, 1H, isoquin.); 8.46 (s, 1H, isoquin.); 9.11 (s, 1H, isoquin.); δC (125 MHz, DMSO-d6): 37.29, 44.56, 105.63, 125.32, 125.59, 126.74, 128.18, 131.33, 137.76, 148.86, 151.31, + 159.28; m/z (ESI): 214 [M+H] . Anal. Calcd for C12H11N3O (213.24): C, 67.59; H, 5.20; N, 19.71. Found: C, 67.68; H, 5.27; N, 19.56. Single crystals of 3e were obtained by crystallization from CHCl3. Diffraction data were collected at room temperature with an Oxford Diffraction SuperNova diffractometer using Cu Kα radiation and processed with CrysAlisPro software [38]. Using Olex2 [39], the structure was solved with the program SHELXT [40] and refined by the full-matrix least-squares method on F2 with SHELXL-2016/6 [41]. Crystal Data for 3e (C12H11N3O, M = 213.24 g/mol): monoclinic, space group P21/c (no. 14), 3 a = 5.9861(1) Å, b = 8.4459(1) Å, c = 20.2004(2) Å, β = 94.6230(10)◦, V = 1017.97(2) Å , Z = 4, T = 294 K, µ(CuKα) = 0.750 mm 1, D = 1.391 g/cm3, 12,358 reflections measured (11.362 2Θ 153.02 ), 2115 − calc ◦ ≤ ≤ ◦ unique (Rint = 0.0205, Rsigma = 0.0101) which were used in all calculations. The final R1 was 0.0350 (I > 2σ(I)) and wR2 was 0.1019 (all data). Illustrations were prepared with the OLEX2 software [39]. CCDC 1,944,714 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: [email protected].

1-(Isoquinolin-3-yl)-1H-benzimidazol-2(3H)-one (3f)

Starting from 0.201 g (1.5 mmol) 1H-benzimidazol-2(3H)-one; yield 3f 0.017 g (13%); reaction time 1 80 h; eluent: dichloromethane:ethyl acetate, (8:2, v/v); m.p. 186–189 ◦C; νmax (KBr, cm− ): 3183, 3138, 3068, 2902, 2838, 1731, 1628, 1594, 1583, 1486, 1454, 1387, 1177, 873, 741, 720; δH (500 MHz, DMSO-d6): 7.05 (t, 1H, arom.); 7.11 (m, 2H, arom.); 7.69 (t, 1H, isoquin.); 7.75 (d, J = 7.7 Hz, 1H, arom.); 7.82 (t, 1H, isoquin.); 8.07 (d, J = 8.3 Hz, 1H, isoquin.); 8.20 (d, J = 8.2 Hz, 1H, isoquin.); 8.35 (s, 1H, isoquin.); 9.38 + (s, 1H, isoquin.); 11.32 (s, 1H, NH); m/z (ESI): 362 [M + H] . Anal. Calcd for C16H11N3O (261.28): C, 73.55; H, 4.24; N, 16.08. Found: C, 73.62; H, 4.36; N, 16.18.

1-(Isoquinolin-3-yl)-5-methoxy-1H-benzimidazol-2(3H)-one (3g) and 1-(isoquinolin-3-yl)-6-methoxy-1H -benzimidazol-2(3H)-one (3h)

Starting from 0.246 g (1.5 mmol) 5-methoxy-1H-benzimidazol-2(3H)-one; yield mixture of 3g and 3h 0.026 g (18%); reaction time 85 h; eluent: dichloromethane:ethyl acetate, (4:1, v/v); m.p. 164–170 ◦C; 1 νmax (KBr, cm− ): 3165, 3056, 2946, 2901, 2832, 1706, 1628, 1611, 1583, 1495, 1450, 1378, 1269, 1199, 1159, 746; δH 3g and 3h (500 MHz, DMSO-d6): 3.72 (s, 3H, OCH3); 3.76 (s, 3H, OCH3); 6.64–6.67 (m, 2H, 2xarom.); 6.71 (dd, J1 = 2.2 Hz, J2 = 8.8 Hz, 1H, arom.); 6.99 (d, J = 8.2 Hz, 1H, arom.); 7.38 (d, J = 2.2 Hz, 1H, arom.); 7.65–7.71 (m, 2H, 2xisoquin.); 7.77 (d, J = 8.8 Hz, 1H, arom.); 7.79–7.84 (m, 2H, 2xisoquin.); 8.04–8.07 (m, 2H, 2xisoquin.); 8.17–8.21 (m, 2H, 2xisoquin.); 8.34 (s, 1H, isoquin.); 8.39 (s, 1H, isoquin.); 9.34 (s, 1H, isoquin.); 9.39 (s, 1H, isoquin.); 11.12 (s, 1H, NH); 11.27 (s, 1H, NH); m/z (ESI): 292 [M + H]+. Anal. Calcd for C17H13N3O2 (291.30): C, 70.09; H, 4.50; N, 14.42. Found: C, 70.31; H, 4.64; N, 14.38.

1.3-Di(isoquinolin-3-yl)imidazolidin-2-one (4a)

Starting from 0.129 g (1.5 mmol) imidazolidin-2-one; yield 4a 0.03 g (35%); reaction time 19 h; 1 eluent: dichloromethane:ethyl acetate, (19:1, v/v); m.p. 218–220 ◦C; νmax (KBr, cm− ): 3053, 2926, 2857, 1720, 1628, 1585, 1443, 1393, 1352, 1291, 1244, 872, 737; δH (500 MHz, DMSO-d6): 4.27 (s, 4H, CH2-CH2); 7.52 (t, 2H, 2xisoquin.); 7.72 (t, 2H, 2 isoquin.); 7.93 (d, J = 8.2 Hz, 2H, 2xisoquin.); 8.06 (d, J = 8.2 Hz, × Molecules 2019, 24, 4070 11 of 16

2H, 2 isoquin.); 8.64 (s, 2H, 2 isoquin.); 9.21 (s, 2H, 2xisoquin.); m/z (ESI): 341 [M + H]+. Anal. Calcd × × for C21H16N4O (340.38): C, 74.10; H, 4.74; N, 16.46. Found: C, 73.89; H, 4.59; N, 16.41.

1.3-Di(isoquinolin-3-yl)-1H-benzimidazol-2(3H)-one (4b)

Starting from 0.201 g (1.5 mmol) 1H-benzimidazol-2(3H)-one; yield 4b 0.005 g (5%); reaction time 1 80 h; eluent: dichloromethane:ethyl acetate, (9:1, v/v); m.p. 277–278 ◦C; νmax (KBr, cm− ): 3055, 2955, 2925, 1717, 1629, 1594, 1583, 1487, 1450, 1397, 1180, 1156, 740; δH (200 MHz, DMSO-d6): 7.21–7.26 (m, 2H, arom.); 7.69–7.80 (m, 4H, arom.+2 isoquin.); 7.89 (t, 2H, 2 isoquin.); 8.13 (d, J = 8.1 Hz, 2H, 2 × × × isoquin.); 8.26 (d, J = 7.9 Hz, 2H, 2 isoquin.); 8.43 (s, 2H, 2xisoquin.); 9.47 (s, 2H, 2 isoquin.); m/z + × × (ESI): 389 [M + H] . Anal. Calcd for C25H16N4O (388.42): C, 77.30; H, 4.15; N, 14.42. Found: C, 77.21; H, 4.03; N, 14.53.

1.3-Di(isoquinolin-3-yl)-5-methoxy-1H-benzimidazol-2(3H)-one (4c)

Starting from 0.246 g (1.5 mmol) 5-methoxy-1H-benzimidazol-2(3H)-one; yield 4c 0.005 g (5%); 1 reaction time 85 h; eluent: dichloromethane:ethyl acetate, (9:1, v/v); m.p. 189–189 ◦C; νmax (KBr, cm− ): 3050, 2988, 2934, 2898, 2828, 1725, 1629, 1582, 1494, 1447, 1394, 1275, 1179, 737; δH (500 MHz, DMSO-d6): 3.76 (s, 3H, OCH3); 6.82 (dd, J1 = 2.2 Hz, J2 = 8.8 Hz, 1H, arom.); 7.35 (d, J = 2.7 Hz, 1H, arom.); 7.71–7.77 (m, 2H, 2 isoquin.); 7.79 (d, J = 8.8 Hz, 1H, arom.); 7.83–7.88 (m, 2H, 2 isoquin.); 8.08–8.12 (m, 2H, × × 2 isoquin.); 8.23–8.26 (m, 2H, 2 isoquin.); 8.40 (s, 1H, isoquin.); 8.44 (s, 1H, isoquin.); 9.43 (s, 1H, × × + isoquin.); 9.46 (s, 1H, isoquin.); m/z (ESI): 419 [M + H] . Anal. Calcd for C26H18N4O2 (418.45): C, 74.63; H, 4.34; N, 13.39. Found: C, 74.76; H, 4.48; N, 13.52.

1-(Isoquinolin-3-yl)-3-methylimidazolidin-2-one (5)

To a stirred compound 3e (0.213 g, 1 mmol) in 1–2 mL of anhydrous DMF was added solid NaOH (0.1 g, 2.5 mmol) and methyl iodide (0.852 g, 6 mmol). After 48 h a mixture was dissolved with chloroform (15 mL) and evaporated to dryness. Compound 5 was separated by use of chromatotron, eluent: dichloromethane:ethyl acetate: methanol, (8:1.5:0.5, v/v/v); yield 5 0.109 g (48%); m.p. 148–150 ◦C; 1 νmax (KBr, cm− ): 3104, 3037, 2917, 2883, 1702, 1626, 1585, 1504, 1487, 1455, 1432, 1387, 1274, 1228, 878, 763, 748, 733; δH (400 MHz, DMSO-d6): 2.82 (s, 3H, CH3), 3.48 (t, 2H, CH2), 4.06 (t, 2H, CH2), 7.46 (t, 1H, isoquin.), 7.66 (t, 1H, isoquin.), 7.84 (d, J = 8.4 Hz, 1H, isoquin.), 8.01 (d, J = 8.3 Hz, 1H, isoquin.), 8.48 (s, 1H, isoquin.), 9.13 (s, 1H, isoquin.); δC (100 MHz, DMSO-d6): 31.20, 41.70, 43.90, 105.24, 125.18, 125.37, 126.49, 127.96, 131.11, 137.55, 148.64, 151.12, 157.55; m/z (ESI, MeOH:0,1% AcOH+ACN, 1:1, v/v): + + 228 [M + H] and 250 [M + Na] . Anal. Calcd for C13H13N3O (227.26): C, 68.70; H, 5.77; N, 18.49. Found: C, 68.48; H, 6.01; N, 18.61.

Synthesis of 1-(Isoquinolin-3-yl)-3-(hetero)aryl-imidazolidin-2-ones 7a-d

To a stirred compound 3e (0.213 g, 1 mmol) in 2–3.5 mL of n-butanol was added appropriate aryl iodide (2–5 mmol), copper(I) iodide (0.019 g; 0.1 mmol), N,N’-dimethylethylenediamine (DMEDA) (0.026 g, 0.3 mmol) and anhydrous potassium carbonate (0.415 g, 3 mmol). A mixture was heated in an oil bath at 90–100 ◦C for 12–90 h. The progress of reaction was controlled by TLC. Then to a mixture were added 5 mL of water and 5 mL of chloroform and solvents were evaporated under reduced pressure. The residue was extracted five times with 10 cm3 portions of chloroform, dried over anhydrous MgSO4, and filtered. The solvent was removed in vacuo and semi-crystalline residue was purified on silica gel by preparative thin layer chromatography by use of chromatotron or 20 20 cm × glass plates (silica gel: 5–17 µm, layer thickness 0.25 mm, medium pore diameter 60Å).

1-(Isoquinolin-3-yl)-3-phenylimidazolidin-2-one (7a) Molecules 2019, 24, 4070 12 of 16

Starting from 1.02 g (5 mmol; 0.56 mL; 1.823 g/mL) of iodobenzene (6a) (added gradually); yield 7a 0.195 g (67%); reaction time 54 h; eluent: chloroform:ethyl acetate, (4:1, v/v); m.p. 212–213 ◦C; νmax 1 (KBr, cm− ): 3060, 3025, 2963, 2904, 1704, 1629, 1598, 1586, 1504, 1454, 1410, 1318, 1290, 1250, 735, 685; δH (300 MHz, CDCl3): 3.98 (t, 2H, CH2), 4.31 (t, 2H, CH2), 7.11 (t, 1H, arom.), 7.36–7.45 (m, 3H, arom.), 7.57–7.67 (m, 3H, arom.), 7.80 (d, J = 8.3 Hz, 1H, arom.), 7.87 (d, J = 8.2 Hz, 1H, arom.), 8.64 (s, 1H, arom.), 9.02 (s, 1H, arom.); δC (75 MHz, CDCl3): 36.23, 37.32, 102.48, 113.41 (two overlapping signals), 118.41, 120.50, 120.81, 121.93, 122.53, 124.14 (two overlapping signals), 125.66, 133.03, 135.18, 142.78, + + 145.58, 150.05; m/z (ESI): 290 [M + H] and 312 [M + Na] . Anal. Calcd for C18H15N3O (289.33): C, 74.72; H, 5.23; N, 14.52. Found: C, 74.56; H, 5.01; N, 14.37.

1-(Isoquinolin-3-yl)-3-(4-methoxyphenyl)imidazolidin-2-one (7b)

Starting from 0.702 g (3 mmol) of 1-iodo-4-methoxybenzene (6b); yield 7b 0.092 g (29%); reaction time 27 h; eluent: chloroform:ethyl acetate, (4:1, v/v); crystallized from methanol; m.p. 166–169 ◦C; 1 νmax (KBr, cm− ): 3003, 2957, 2927, 2847, 1692, 1624, 1581, 1514, 1479, 1461, 1432, 1288, 1247, 1039, 824; δH (300 MHz, CDCl3): 3.81 (s, 3H, OCH3), 3.95 (t, 2H, CH2), 4.30 (t, 2H, CH2), 6.94 (d, J = 9.0 Hz, 1H, arom.), 7.41 (t, 1H, arom.), 7.54 (d, J = 9.2 Hz, 2H, arom.), 7.59 (t, 1H, arom.), 7.79 (d, J = 8.3, 1H, arom.), 7.86 (d, J = 8.2, 1H, arom.), 8.63 (s, 1H, arom.), 9.01 (s, 1H, arom.); δC (75 MHz, CDCl3): 41.07, 42.58, 55.51, 107.07, 114.16 (two overlapping signals), 120.19 (two overlapping signals), 125.16, 125.49, 126.67, 127.28, 130.38, 133.19, 137.81, 147.70, 150.30, 155.05, 155.81; m/z (ESI): 320 [M + H]+ and 342 [M + Na]+. Anal. Calcd for C19H17N3O2 (319.36): C, 71.46; H, 5.37; N, 13.16. Found: C, 71.38; H, 5.34; N, 12.98.

1-(Isoquinolin-3-yl)-3-(4-nitrophenyl)imidazolidin-2-one (7c)

Starting from 0.5 g (2 mmol) of 1-iodo-4-nitrobenzene (6c); yield 7c 0.019 g (6%); reaction time 71 h; eluent: petrol ether:chloroform, (1:1, v/v) and chloroform:ethyl acetate, (4:1, v/v); m.p. 187–189 ◦C; 1 νmax (KBr, cm− ): 3126, 2955, 2925, 2854, 1710, 1630, 1597, 1507, 1478, 1401, 1327, 1309, 1286, 1246, 1114, 842, 750, 735; δH (300 MHz, DMSO-d6): 4.06–4.11 (m, 2H, CH2), 4.24–4.29 (m, 2H, CH2), 7.52 (t, 1H, arom.), 7.71 (t, 1H, arom.), 7.88–7.94 (m, 3H, arom.), 8.05 (d, J = 8.3 Hz, 1H, arom.), 8.26 (d, J = 9.1, 2H, arom.), 8.55 (s, 1H, arom.), 9.19 (s, 1H, arom.); m/z (ESI): 335 [M+H]+ and 357 [M + Na]+. Anal. Calcd for C18H14N4O3 (334.33): C, 64.66; H, 4.22; N, 16.76. Found: C, 64.58; H, 4.12; N, 16.64.

1-(Isoquinolin-3-yl)-3-(pyridin-2-yl)imidazolidin-2-one (7d)

Starting from 0.41 g (2 mmol; 0.213 mL; 1.928 g/mL) of 2-iodopyridine (6d); yield 7d 0.176 g (61%); reaction time 49 h; eluent: chloroform and chloroform:ethyl acetate, (4:1, v/v); crystallized from 1 methanol; m.p. 208–209 ◦C; νmax (KBr, cm− ): 3117, 3062, 3000, 2917, 1712, 1627, 1589, 1473, 1435, 1389, 1357, 1287, 1244, 1136, 778, 740; δH (300 MHz, CDCl3): 4.17–4.33 (m, 4H, CH2-CH2), 6.96–7.00 (m, 1H, arom.), 7.43 (t, 1H, arom.), 7.60 (t, 1H, arom.), 7.69 (t, 1H, arom.), 7.81 (d, J = 8.4 Hz, 1H, arom.), 7.87 (d, J = 8.2 Hz, 1H, arom.), 8.34 (dd, J1 = 1.2 Hz, J2 = 4.4 Hz, 1H, arom.), 8.33–8.39 (m, 2H, arom.), 8.62 (s, 1H, arom.), 9.03 (s, 1H, arom.); δC (75 MHz, CDCl3): 40.77, 41.07, 107.44, 113.30, 118.17, 125.39, 125.69, 126.68, 127.29, 130.42, 137.37, 137.70, 147.30, 147.50, 150.46, 152.22, 154.52; m/z (ESI): 291 [M+H]+ and + m/z = 313 [M + Na] . Anal. Calcd for C17H14N4O (290.32): C, 70.33; H, 4.86; N, 19.30. Found: C, 70.21; H, 4.78; N, 19.22. n-Butyl 3-(Isoquinolin-3-ylamino)propanoate (8)

To a stirring solution of 3-bromoisoquinoline (0.208 g, 1 mmol) in n-butanol (2–3 cm3) was added azetidin-2-one (0.213 g, 3 mmol), potassium carbonate (0.415 g, 3 mmol), copper(I) iodide (0.019 g, 0.1 mmol) and N,N-dimethylethylenediamine (DMEDA) (0.026 g, 0.3 mmol). A mixture was heated in an oil bath at 100 ◦C for 3 h. The progress of reaction was controlled by TLC. The mixture was then Molecules 2019, 24, 4070 13 of 16 evaporated under reduced pressure and the residue was extracted ﬁve times with 10 cm3 portions of chloroform, dried over anhydrous MgSO4, and ﬁltered. The solvent was removed in vacuo and the residue was dissolved in chloroform (3–5 cm3). Compound 8 was isolated on silica gel by preparative thin layer chromatography (chromatotron, eluent: diethyl ether:petrol ether, 6:4, v/v); green crystals; 1 yield 0.11 g (40%); m.p. 65–67 ◦C; νmax (KBr, cm− ): 3278, 3059, 2959, 2894, 2870, 1736, 1629, 1594, 1543, 1479, 1403, 1363, 1318, 1181, 1105; 810, 749; δH (500 MHz, DMSO-d6): 0.85 (t, 3H, CH3); 1.29 (sxt, 2H, CH2); 1.52 (qui, 2H, CH2); 2.62 (t, 2H, CH2); 3.50 (q, 2H, CH2); 4.02 (t, 2H, CH2); 6.47 (t, 1H, NH); 6.60 (s, 1H, isoquin.); 7.15 (t, 1H, isoquin.); 7.45 (t, 1H, isoquin.); 7.55 (d, J = 8.2 Hz, 1H, isoquin.); 7.79 (d, J = 8.2 Hz, 1H, isoquin.); 8.85 (s, 1H, isoquin.); δC (125 MHz, DMSO-d6): 14.01, 19.07, 30.62, 34.37, 38.19, 64.06, 96.37, 122.28, 123.01, 124.85, 128.16, 130.61, 138.90, 151.80, 156.05, 172.24; m/z (ESI): 273 [M + H]+. Anal. Calcd for C16H20N2O2 (272.34): C, 70.56; H, 7.40; N, 10.29. Found: C, 70.42; H, 7.28; N, 10.34.

3-(Isoquinolin-3-ylamino)-1-(pyrrolidin-1-yl)propan-1-one (9)

To a solution of n-butyl 3-(isoquinolin-3-ylamino)propanoate (8) (0.095 g, 0.35 mmol) in ethanol (3 cm3) was added pyrrolidine (0.075 g, 1.05 mmol). A mixture was stirred under reﬂux (oil bath at 3 90–100 ◦C) for 17 h and evaporated in vacuo. Crude product was extracted four times with 10 cm portions of chloroform, dried over anhydrous MgSO4, and ﬁltered. The solvent was removed under reduced pressure and the oily residue was dissolved in chloroform (3 cm3). Compound 9 was isolated on silica gel by preparative thin layer chromatography (chromatotron, eluent: ethyl acetate:methanol, 1 9:1, v/v); green powder; yield 0.05 g (53%); m.p. 141–143 ◦C; νmax (KBr, cm− ): 3280, 3064, 2970, 2872, 1646, 1627, 1593, 1545, 1438, 1220, 814, 752; δH (500 MHz, DMSO-d6): 1.74 (qui, 2H, CH2); 1.83 (qui, 2H, CH2); 2.56 (t, 2H, CH2); 3.28 (t, 2H, CH2); 3.37 (t, 2H, CH2); 3.46 (q, 2H, CH2); 6.35 (t, 1H, NH); 6.59 (s, 1H, isoquin.); 7.14 (t, 1H, isoquin.); 7.45 (t, 1H, isoquin.); 7.54 (d, J = 8.3 Hz, 1H, isoquin.); 7.78 (d, + J = 8.3 Hz, 1H, isoquin.); 8.84 (s, 1H, isoquin.); m/z (ESI): 270 [M + H] . Anal. Calcd for C16H19N3O (269.34): C, 71.35; H, 7.11; N, 15.60. Found: C, 71.51; H, 6.98; N, 15.74.

4. Conclusions In conclusion, we synthesized novel isoquinoline derivatives substituted at position 3 of the heteroaromatic ring in Goldberg–Ullmann-type coupling with appropriate amides in the presence of copper(I) iodide and N,N-dimethylethylenediamine (DMEDA). Optimization of the coupling reaction of 3-bromoisoquinoline with a series of lactams and imidazolidinones was studied at different temperatures and various solvents. It was found that the higher conversion of starting materials and better yields of desired products were achieved using n-butanol. The isoquinolines 3a–e and N-methyl derivative 5 studied in this report displayed promising fluorescent properties. Compounds 3a, 3c, and 3e possess a higher fluorescence quantum yield (Φf = from 63.4% to 96.3%) in an acidic aqueous solution than quinine hemisulfate (Φf = 57.7%) used as a reference standard. Interestingly, compound 3e with a secondary amide group offering an anchoring group is a prominent scaffold for further functionalization. Moreover, 1-(isoquinolin-3-yl)imidazolidin-2-one (3e) displayed the highest molar extinction coefficient (5083 1 1 M− cm− ). The highest quantum yield value (Φf = 96.3%) was measured for derivative containing β-lactam ring 3a. This may be connected with the structural rigidity of this compound. Although these are preliminary results, novel isoquinoline derivatives 3a–e and 5 constitute a promising group of fluorescent compounds with potential applications in medicinal chemistry.

Supplementary Materials: Supplementary data including 1H nmR spectra for novel compounds as well as absorption and ﬂuorescence spectra of selected compounds associated with this article are available online. CCDC 1944714 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: [email protected]. Molecules 2019, 24, 4070 14 of 16

Author Contributions: F.S. and Ł.B. conceived and designed the experiments; Ł.B., K.C. and A.J. performed the experiments; M.G. analyzed the data; Ł.B., A.K. and M.G. wrote the paper. Funding: This research was supported by the Funds for Statutory Activity of the Medical University of Gdańsk (ST-020038/07). Acknowledgments: The nmR spectra were carried out at The Nuclear Magnetic Resonance Laboratory, Gdańsk University of Technology, Poland and The Nuclear Magnetic Resonance Spectroscopy Laboratory, Collegium Medicum, Jagielonian University, Kraków, Poland. Conflicts of Interest: The authors declare no conflict of interest.

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