Regioselective Synthesis of New Family of 2-Substituted 1,2,3-Triazoles and Study of Their Fluorescent Properties

Modification of 5-aryl-4-trifluoroacetyltriazoles at the NH-moiety was investigated. Screening of the alkylation conditions revealed that using Na2CO3 as a base and DMF as a solvent of 2-substituted triazoles can be preferentially prepared in up to 86% yield. In the best cases, the amount of minor 1-alkyl isomer was less than 6%. SNAr reaction of the 5-aryl-4-trifluoroacetyltriazoles with aryl halides having electron-withdrawing groups led to regiospecific formation of 2-aryltriazoles isolated in good-to-high yields. Chan–Lam reaction of the 5-aryl-4-trifluoroacetyltriazoles with boronic acids afforded 2-aryltriazoles as single isomers in up to 89% yield. The subsequent reaction of the prepared 2-aryltriazoles with primary and secondary amines gave a set of amides of 4-(2,5-diaryltriazolyl)carboxylic acid. The fluorescent properties of the prepared 2-substituted derivatives of triazoles were investigated to demonstrate their utility as new efficient luminophores having more than 60% quantum yields.

The most reliable strategy towards fluorinated compounds is a building block strategy, which uses the assembling of simple fluorinated molecules into more complex structures. Last year, our group was tightly engaged with the elaboration and investigation of novel fluorinated building blocks to prepare various trifluoromethylated heterocycles. Thus, we have proposed convenient syntheses of α-CF 3 -β-aryl enamines [31], α,β-diaryl-CF 3enones [32] and CF 3 -ynones [33], which appeared to be versatile CF 3 -building blocks for the synthesis of various fluorinated compounds [34,35]. Recently, we have found that reaction of CF 3 -ynones with sodium azide can be used for directed synthesis of either 5-CF 3 -isoxazoles or previously unknown 4-trifluoroacetyltriazoles [36]. The prepared triazoles are a new class of triazolyl compounds. In this article, we have investigated the reactivity and regioselectivity of 4-trifluoroacetyltriazoles in alkylation and arylation as well as the fluorescent properties of the prepared derivatives.

Results
As a starting point, we studied alkylation of the model triazole 1a in DMF by using benzyl chloride and bromide with Na 2 CO 3 as a base. We found that both reagents af-Next, we tested several bases in the reaction. We found that application of Li2CO3, Na2CO3 and K2CO3 provided similar selectivity and yields. Use of Cs2CO3 and DBU gave triazoles less selectively and in significantly lower yield. In the case of NaH, alkylated triazoles 3a and 4a were not obtained at all, while the starting material was completely consumed (Scheme 1). Recently, we have demonstrated that the trifluoroacetyl group can be transformed into carboxylic or amide function by heating in basic conditions [37]. We believed that a similar transformation of the trifluoroacetyl group takes place in the case of Cs2CO3, DBU and NaH, leading to formation of a complex reaction mixture. Moreover, Na2CO3 showed the best results in terms of yield and selectivity and has been chosen as a base for further investigations. Using Na2CO3, we investigated the influence of the solvent on the reaction. It was found that the reaction can proceed in both protic and aprotic solvents to give N-alkylated triazoles in good-to-high yields. The highest yields (84%) and selectivity (only 17% of minor isomer) were observed in polar aprotic solvents (DMF, DMSO). Reaction in polar protic solvents (EtOH, H2O) was less selective and produced 30-40% of the isomer 4a. It should be noted that in all investigated solvents, the yields of triazoles did not drop lower than 57%. Taking into account the obtained results, we chose DMF as a solvent and Na2CO3 as a base for all subsequent transformations (Scheme 1).
Having in hand the suitable conditions, we performed reactions with a number of alkyl halides 2. It was found that the product distribution is dependent on the activity of the alkylating agent. Thus, the reactions of triazoles 1a,b with benzyl bromide as well as the reaction of triazole 1a with 4-nitrobenzyl bromide led to a mixture of isomers 3 and 4 Scheme 1. Screening of the reaction conditions for alkylation of triazole 1a with benzyl bromide and chloride.
Next, we tested several bases in the reaction. We found that application of Li 2 CO 3 , Na 2 CO 3 and K 2 CO 3 provided similar selectivity and yields. Use of Cs 2 CO 3 and DBU gave triazoles less selectively and in significantly lower yield. In the case of NaH, alkylated triazoles 3a and 4a were not obtained at all, while the starting material was completely consumed (Scheme 1). Recently, we have demonstrated that the trifluoroacetyl group can be transformed into carboxylic or amide function by heating in basic conditions [37]. We believed that a similar transformation of the trifluoroacetyl group takes place in the case of Cs 2 CO 3 , DBU and NaH, leading to formation of a complex reaction mixture. Moreover, Na 2 CO 3 showed the best results in terms of yield and selectivity and has been chosen as a base for further investigations. Using Na 2 CO 3 , we investigated the influence of the solvent on the reaction. It was found that the reaction can proceed in both protic and aprotic solvents to give N-alkylated triazoles in good-to-high yields. The highest yields (84%) and selectivity (only 17% of minor isomer) were observed in polar aprotic solvents (DMF, DMSO). Reaction in polar protic solvents (EtOH, H 2 O) was less selective and produced 30-40% of the isomer 4a. It should be noted that in all investigated solvents, the yields of triazoles did not drop lower than 57%. Taking into account the obtained results, we chose DMF as a solvent and Na 2 CO 3 as a base for all subsequent transformations (Scheme 1).
Having in hand the suitable conditions, we performed reactions with a number of alkyl halides 2. It was found that the product distribution is dependent on the activity of the alkylating agent. Thus, the reactions of triazoles 1a,b with benzyl bromide as well as the reaction of triazole 1a with 4-nitrobenzyl bromide led to a mixture of isomers 3 and 4 in 81:19 ratio. The reaction of allyl chloride, which compared to benzyl bromide by activity, afforded an 83:17 mixture of isomers. The reaction of MeI (most reactive among non-functionalized alkyl halides) with 1a led to a mixture of 3e and 4e in an 83:17 ratio. The reaction with less reactive aliphatic alkyl bromides proceeds more selectively to give only Molecules 2023, 28, 4822 3 of 21 a 6-9% admixture of minor regioisomer. It should be noted that the reaction outcome is not sensitive to bulkiness of the reagents to give similar results for primary, secondary and cyclic alkyl bromides. However, heating is needed in the case of most bulky iso-propyl-, cyclo-hexyl bromides and iso-butyl chloride. A lower selectivity was observed in the case of the reaction with 1,4-dibromobutane; such a ratio of regioisomers can be explained by statistical factor.
Another type of the alkylating agents investigated were derivatives of 2-haloacetic acid. The alkylation of triazole 1a with ethyl bromoacetate and 2-chloro-N,N-dimethylacetamide gave a mixture of isomeric triazoles in almost the same ratio (90:10 and 89:11, correspondingly). Eventually, sulfonylation of 1a by MsCl and TsCl led to 2-substituted triazoles exclusively (Scheme 2).
Molecules 2023, 28, x FOR PEER REVIEW 3 of 22 in 81:19 ratio. The reaction of allyl chloride, which compared to benzyl bromide by activity, afforded an 83:17 mixture of isomers. The reaction of MeI (most reactive among nonfunctionalized alkyl halides) with 1a led to a mixture of 3e and 4e in an 83:17 ratio. The reaction with less reactive aliphatic alkyl bromides proceeds more selectively to give only a 6-9% admixture of minor regioisomer. It should be noted that the reaction outcome is not sensitive to bulkiness of the reagents to give similar results for primary, secondary and cyclic alkyl bromides. However, heating is needed in the case of most bulky iso-propyl-, cyclo-hexyl bromides and iso-butyl chloride. A lower selectivity was observed in the case of the reaction with 1,4-dibromobutane; such a ratio of regioisomers can be explained by statistical factor. Another type of the alkylating agents investigated were derivatives of 2-haloacetic acid. The alkylation of triazole 1a with ethyl bromoacetate and 2-chloro-N,N-dimethylacetamide gave a mixture of isomeric triazoles in almost the same ratio (90:10 and 89:11, correspondingly). Eventually, sulfonylation of 1a by MsCl and TsCl led to 2-substituted triazoles exclusively (Scheme 2). Next, we switched our attention to the reaction of triazoles 1a with aryl halides activated by electron-withdrawing substituents. In contrast to the SN2 reaction with alkyl halides 2, the SNAr reaction with aryl halides proceeds at elevated temperatures (90-100 °C). Only the reaction with highly reactive 1-fluoro-2,4-dinitrobenzene can be performed at room temperature. The arylation is regiospecific to afford only 2-aryl substituted products 5-12, which is a favorable feature of the arylation. Using this approach, we prepared a set of 2-N arylated triazoles having CF3, NO2 and CO2Et groups in up to 86% yield. In addition, triazole 9 bearing a quinoline moiety was also prepared in moderate yield (Scheme 3).
In spite of the high utility of the SNAr reaction, obvious restriction of this method is necessary in order to have an activating EWG group in the structure of the aryl halide. Therefore, we also investigated an alternative type of arylation of triazoles 1 in conditions of the Chan-Lam reaction. Carried out in open air (no balloons with oxygen and etc.) reactions of triazoles 1 with boronic acids in DMSO at heating under catalysis with copper (II) acetate afforded 2-N-aryl derivatives 12-20 in 100% regioselectively in up to 89% yields Next, we switched our attention to the reaction of triazoles 1a with aryl halides activated by electron-withdrawing substituents. In contrast to the S N 2 reaction with alkyl halides 2, the S N Ar reaction with aryl halides proceeds at elevated temperatures (90-100 • C). Only the reaction with highly reactive 1-fluoro-2,4-dinitrobenzene can be performed at room temperature. The arylation is regiospecific to afford only 2-aryl substituted products 5-12, which is a favorable feature of the arylation. Using this approach, we prepared a set of 2-N arylated triazoles having CF 3 , NO 2 and CO 2 Et groups in up to 86% yield. In addition, triazole 9 bearing a quinoline moiety was also prepared in moderate yield (Scheme 3).
In spite of the high utility of the S N Ar reaction, obvious restriction of this method is necessary in order to have an activating EWG group in the structure of the aryl halide. Therefore, we also investigated an alternative type of arylation of triazoles 1 in conditions of the Chan-Lam reaction. Carried out in open air (no balloons with oxygen and etc.) reactions of triazoles 1 with boronic acids in DMSO at heating under catalysis with copper (II) acetate afforded 2-N-aryl derivatives 12-20 in 100% regioselectively in up to 89% yields (Scheme 4). It should be noted that no additives of any ligands were needed for successful transformation of triazoles 1.
Recently, we found that N-unsubstituted 4-trifluoroacetyl triazoles react with secondary amines at elevated temperatures to produce corresponding amides as a result of formal substitution of CHF3 [37]. The prepared 2-arylated triazoles can be used for the similar transformation as well. We performed the reaction of 2-phenyl substituted triazole 12 with some secondary and primary amines at heating. As a result, a set of amides 21-24 was obtained in good-to-high yields to provide a broad diversity of the synthesized triazole derivatives. Thus, we succeeded in preparing derivatives of pyrrolidine, piperidine, morpholine and n-hexylamine (Scheme 5). Taking into account the literature data [37], we proposed a possible mechanism of the reaction. First, the addition of amine to the carbonyl group of 12 led to intermediate 25. Next, 25 eliminates the trifluoromethyl anion to afford amides 21-24; protonation of CF3-anion gives CF3H. The 1,2,3-triazole scaffold has been intensively investigated in recent decades, boosted by the discovery of CuAAC-RuAAC reactions (metal-catalyzed alkyne-azide cycloaddition) [39,40]. Many 1,2,3-triazoles have useful practical properties and have found applications as agrochemicals, pigments, metal chelators, photostabilizers and corrosion inhibitors [41]. Many 1,2,3-triazoles are physiologically active compounds and have pharmaceutical and therapeutic applications [42][43][44]. Ion(s) detection capabilities of 1,2,3-triazole ligands using absorption and fluorescence spectroscopy were also reported [45][46][47][48]. Of special interest are 2-Aryl-substituted 1,2,3-triazoles, since these compounds are highly efficient UV/blue-light-emitting fluorophores [49,50]. Therefore, we investigated some photophysical properties of the prepared 2-substituted triazoles. Electronic absorption spectra (c = 10 −5 M) and fluorescence spectra data were recorded in methanol solutions (c = 10 −6 M) at room temperature. The quantum yields of fluorescence (φ) were determined by a comparative method using 2-aminopyridine as the standard. The absorption band of compounds 3 bearing alkyl group in the position 2 of triazole has one pronounced peak; however, tosyl-substituted triazole 3q has several adsorption bands. The adsorption maxima of 3a,d,e,p,r are in the range of 224-234 nm ( Figure 2a). All these derivatives demonstrated light emission in the range 297-303 nm and quantum yields below 10% (Table 1, Figure 2b). The 1,2,3-triazole scaffold has been intensively investigated in recent decades, boosted by the discovery of CuAAC-RuAAC reactions (metal-catalyzed alkyne-azide cycloaddition) [39,40]. Many 1,2,3-triazoles have useful practical properties and have found applications as agrochemicals, pigments, metal chelators, photostabilizers and corrosion inhibitors [41]. Many 1,2,3-triazoles are physiologically active compounds and have pharmaceutical and therapeutic applications [42][43][44]. Ion(s) detection capabilities of 1,2,3-triazole ligands using absorption and fluorescence spectroscopy were also reported [45][46][47][48]. Of special interest are 2-Aryl-substituted 1,2,3-triazoles, since these compounds are highly efficient UV/blue-light-emitting fluorophores [49,50]. Therefore, we investigated some photophysical properties of the prepared 2-substituted triazoles. Electronic absorption spectra (c = 10 −5 M) and fluorescence spectra data were recorded in methanol solutions (c = 10 −6 M) at room temperature. The quantum yields of fluorescence (ϕ) were determined by a comparative method using 2-aminopyridine as the standard. The absorption band of compounds 3 bearing alkyl group in the position 2 of triazole has one pronounced peak; however, tosyl-substituted triazole 3q has several adsorption bands. The adsorption maxima of 3a,d,e,p,r are in the range of 224-234 nm ( Figure 2a). All these derivatives demonstrated light emission in the range 297-303 nm and quantum yields below 10% (Table 1, Figure 2b).  Much more interesting photophysical properties are observed for 2-aryl substituted triazoles 6-24. Among these types of triazoles, we found highly efficient fluorophores demonstrating emission in the range 335-368 nm and quantum yields up to 65% in methanol solution. However, it was found that the nature of the substituent in the 2-aryl group of triazoles 6 influences dramatically the emission properties ( Table 2). For example, compounds 6-8, 11 do not fluoresce at all. Complete quenching of fluorescence in these cases can be explained by the presence of the EWG group at the aryl fragment attached to the position 2 of the triazole. In contrast, high quantum yields are observed when the aryl group at the position 2 is electron-rich. The absorption spectra of compounds 6,7,10,11,13,20 have two bands, which is especially pronounced for compounds 7,10. The introduction of an electron-withdrawing group into the 2-aryl substituent leads to a bathochromic shift of the absorption band. It is most pronounced for compounds 6 and 7 (Figure 3a). The exception is 10, for which a slight hypsochromic shift is observed. At the same time, despite the low quantum yield, 10 has the largest Stokes shift among the compounds of this series (Figure 3b). Most probably, this is due to the influence of its fluorinated fragment. The introduction of substituents into the para-position of 5-aryltriazole does not affect significantly the position of the absorption band, causing only a slight bathochromic shift for 13 ( Figure 4a). The quantum yields of 12-20 compounds turned out to be the best among the N-2-aryl-1,2,3-triazoles studied by us and are in the range of 0.23-0.65 ( Figure  4b). The highest value for compound 15, for compounds 14, 16-20, is about 0.60. Much more interesting photophysical properties are observed for 2-aryl substituted triazoles 6-24. Among these types of triazoles, we found highly efficient fluorophores demonstrating emission in the range 335-368 nm and quantum yields up to 65% in methanol solution. However, it was found that the nature of the substituent in the 2-aryl group of triazoles 6 influences dramatically the emission properties (Table 2). For example, compounds 6-8, 11 do not fluoresce at all. Complete quenching of fluorescence in these cases can be explained by the presence of the EWG group at the aryl fragment attached to the position 2 of the triazole. In contrast, high quantum yields are observed when the aryl group at the position 2 is electron-rich. The absorption spectra of compounds 6,7,10,11,13,20 have two bands, which is especially pronounced for compounds 7,10. The introduction of an electron-withdrawing group into the 2-aryl substituent leads to a bathochromic shift of the absorption band. It is most pronounced for compounds 6 and 7 ( Figure 3a). The exception is 10, for which a slight hypsochromic shift is observed. At the same time, despite the low quantum yield, 10 has the largest Stokes shift among the compounds of this series ( Figure 3b). Most probably, this is due to the influence of its fluorinated fragment. The introduction of substituents into the para-position of 5-aryltriazole does not affect significantly the position of the absorption band, causing only a slight bathochromic shift for 13 ( Figure 4a). The quantum yields of 12-20 compounds turned out to be the best among the N-2-aryl-1,2,3-triazoles studied by us and are in the range of 0. 23      The spectral characteristics of amides 21-24 are presented in Table 3. The maximum of the absorption band is in the range of 286-290 nm. These types of triazoles demonstrate emission in the region of 340-345 nm and quantum yields up to 26%. In spite of structural similarity, the influence of amine is very pronounced. For example, compound 21 has a rather high extinction coefficient of 29,740 L·mol −1 ·cm −1 , and compound 24 has the highest quantum yield of 26% among the amides obtained ( Figure 5).  The spectral characteristics of amides 21-24 are presented in Table 3. The maximum of the absorption band is in the range of 286-290 nm. These types of triazoles demonstrate emission in the region of 340-345 nm and quantum yields up to 26%. In spite of structural similarity, the influence of amine is very pronounced. For example, compound 21 has a rather high extinction coefficient of 29,740 L·mol −1 ·cm −1 , and compound 24 has the highest quantum yield of 26% among the amides obtained ( Figure 5).  Thus, the absorption and emission range of all studied compounds is in the ultraviolet region, and 12-19 compounds have sufficiently high quantum yields.

Materials and Methods
In general, 1 H, 13 C and 19 F NMR spectra were recorded on Bruker AVANCE 400 MHz spectrometer in CD3CN and CDCl3 at 400.1, 100.6 and 376.5 MHz, respectively. Chemical shifts (δ) in ppm are reported with the use of the residual CHD2CN and chloroform signals (1.94, 7.25 for 1 H and 1.30, 77.0 for 13 C) as internal reference. The 19 F chemical shifts were referenced to C6F6 (−162.9 ppm). The coupling constants (J) are given in Hertz (Hz). HRMS spectra were measured on the MicroTof Bruker Daltonics instrument. TLC analysis was performed on "Macherey-Nagel ALUGRAM Xtra SIL G/UV254" plates. Column chromatography was performed on silica gel "Macherey-Nagel 0.063-0.2 nm (Silica 60)". All reagents were of reagent grade and were used as such or were distilled prior to use. Triazoles 1 were prepared as reported previously [43]. Melting points were determined on the Electrothermal 9100 apparatus (Electrothermal, Stone, Staffordshire, UK). Electronic absorption spectra were recorded on Genesys 50 (Thermo Scientific) in cuvettes with an optical path length of 1 cm at room temperature using methanol as a solvent. Emission spectra were recorded with a Hitachi F2700 spectrofluorometer (Hitachi, Tokyo, Japan) in 1 cm quartz cuvettes. The relative fluorescence quantum yields (φ) were measured using 2-aminopyridine 0.1 M H2SO4 (φ = 0.60) as a standard. [51] Screening of the optimal conditions for modification of triazoles 1 by alkylating reagents. A 4 mL vial with a screw cap was charged with triazole 1a (0.060 g, 0.25 mmol), solvent (0.5 mL), base (0.38 mmol, 1.5 equiv.) and corresponding alkylating reagent (0.275 mmol, 1.1 equiv., 0.035 g (BnCl) or 0.047 g(BnBr)). The reaction mixture was stirred at room temperature overnight. The yields and ratio of 3a and 4a were determined by 19 F NMR using PhCF3 as an internal standard. Thus, the absorption and emission range of all studied compounds is in the ultraviolet region, and 12-19 compounds have sufficiently high quantum yields.

Materials and Methods
In general, 1 H, 13 C and 19 F NMR spectra were recorded on Bruker AVANCE 400 MHz spectrometer in CD 3 CN and CDCl 3 at 400.1, 100.6 and 376.5 MHz, respectively. Chemical shifts (δ) in ppm are reported with the use of the residual CHD 2 CN and chloroform signals (1.94, 7.25 for 1 H and 1.30, 77.0 for 13 C) as internal reference. The 19 F chemical shifts were referenced to C 6 F 6 (−162.9 ppm). The coupling constants (J) are given in Hertz (Hz). HRMS spectra were measured on the MicroTof Bruker Daltonics instrument. TLC analysis was performed on "Macherey-Nagel ALUGRAM Xtra SIL G/UV 254 " plates. Column chromatography was performed on silica gel "Macherey-Nagel 0.063-0.2 nm (Silica 60)". All reagents were of reagent grade and were used as such or were distilled prior to use. Triazoles 1 were prepared as reported previously [43]. Melting points were determined on the Electrothermal 9100 apparatus (Electrothermal, Stone, Staffordshire, UK). Electronic absorption spectra were recorded on Genesys 50 (Thermo Scientific) in cuvettes with an optical path length of 1 cm at room temperature using methanol as a solvent. Emission spectra were recorded with a Hitachi F2700 spectrofluorometer (Hitachi, Tokyo, Japan) in 1 cm quartz cuvettes. The relative fluorescence quantum yields (ϕ) were measured using 2-aminopyridine 0.1 M H 2 SO 4 (ϕ = 0.60) as a standard. [51] Screening of the optimal conditions for modification of triazoles 1 by alkylating reagents. A 4 mL vial with a screw cap was charged with triazole 1a (0.060 g, 0.25 mmol), solvent (0.5 mL), base (0.38 mmol, 1.5 equiv.) and corresponding alkylating reagent (0.275 mmol, 1.1 equiv., 0.035 g (BnCl) or 0.047 g(BnBr)). The reaction mixture was stirred at room temperature overnight. The yields and ratio of 3a and 4a were determined by 19 F NMR using PhCF 3 as an internal standard.
Reaction of triazoles (1) with alkylating reagents (general procedure). A 4 mL vial with a screw cap was charged with corresponding triazole 1 (0.5 mmol), DMF (1 mL), Na 2 CO 3 (80 mg, 0.38 mmol, 1.5 equiv.) and corresponding alkylating reagent (0.55 mmol, 1.1 equiv.) The reaction mixture was stirred at room temperature overnight or heated (8 h at 80 • C for 3l, 14 h at 100 • C for 3k, 16h at 100 • C for 3m) and then was broken by 0.1 M HCl (20 mL). The product was extracted by CH 2 Cl 2 (3 × 10 mL); the organic phase was washed with water (2 × 10 mL), brine (10 mL) and dried over Na 2 SO 4 . Volatiles were evaporated in vacuo; the residue formed was purified by column chromatography on silica gel using gradient eluation by hexane-CH 2 Cl 2 mixture (3:1) followed by hexane-CH 2 Cl 2 mixture (1:1) and CH 2 Cl 2 . Evaporation of the solvents afforded corresponding pure triazole 3. Due to low amounts of minor triazoles 4, these compounds were not separated completely from major triazoles 3 in some cases. Mostly 1 H NMR and 19 NMR were measured for 3. Only the most characteristic signals of 3 are given in 13 C NMR.

Conclusions
In conclusion, we investigated modification of 5-aryl-4-trifluoroacetyl-1,2,3-triazoles at NH-moiety. We found that alkylation can be performed selectively in DMF using Na 2 CO 3 as a base. The reaction proceeds at room temperature to produce selectively 2-isomers in high yields as major isomers. The selectivity of the reaction reaches a 94:6 ratio of 2-and 1-isomers. Activated by electron-withdrawing groups, aryl halides react regioselectively to form 2-aryltriazoles in good-to-high yields. Similarly, the copper catalyzed reaction with boronic acids led to 2-aryltriazoles exclusively. Transformation of the latter compounds into amides of 4-(2,5-diaryltriazolyl)carboxylic acid were achieved by heating with primary and secondary amines. Fluorescent properties of prepared 2-derivatives of 1,2,3-triazoles were investigated to reveal that some of them have quantum yields of more than 60%.