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Article

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

by
Vasiliy M. Muzalevskiy
,
Zoia A. Sizova
and
Valentine G. Nenajdenko
*
Department of Chemistry, Lomonosov Moscow State University, 119899 Moscow, Russia
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(12), 4822; https://doi.org/10.3390/molecules28124822
Submission received: 24 May 2023 / Revised: 7 June 2023 / Accepted: 13 June 2023 / Published: 16 June 2023
(This article belongs to the Special Issue Recent Advances in the Use of Azoles in Medicinal Chemistry)
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Abstract

:
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.

1. Introduction

Nowadays, chemistry of fluorinated compounds is one of the most rapidly growing areas of modern organic chemistry [1,2,3,4]. Fluorinated compounds are widely used as construction materials, components of liquid crystalline compositions, agrochemicals and pharmaceuticals [5,6,7,8,9,10]. By some estimations, about 20% of currently used drugs [11,12,13,14,15,16,17,18,19] contain at least one fluorine atom [20]. In 2022, approximately 21% (four out of nineteen) of “small-molecule drugs” approved by the FDA are fluorinated compounds [21]. On the other hand, about 59% of all small-molecule drugs have a nitrogen heterocyclic motif [22]. Last year revealed that four out of every five small-molecule drugs approved by the FDA in 2022 (16 out of 19) are representatives of that class [21]. It is no doubt that elaboration of novel pathways to fluorinated nitrogen heterocycles is of great demand [23,24,25,26,27,28,29,30].
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-CF3-β-aryl enamines [31], α,β-diaryl-CF3-enones [32] and CF3-ynones [33], which appeared to be versatile CF3-building blocks for the synthesis of various fluorinated compounds [34,35]. Recently, we have found that reaction of CF3-ynones with sodium azide can be used for directed synthesis of either 5-CF3-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.

2. Results

As a starting point, we studied alkylation of the model triazole 1a in DMF by using benzyl chloride and bromide with Na2CO3 as a base. We found that both reagents afforded benzylated triazoles 3a and 4a in high total yield. Moreover, the reaction proceeds regioselectively to form the 2-isomeric triazole 3a preferentially (Scheme 1).
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 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 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).
Elucidation of the structure of regioisomers 3 and 4 was carried out by comparison with the literature data. Previously, we have found that 2 + 3 cycloaddition reaction of CF3-ynones with alkyl and aryl azides led mostly to 1-substituted triazoles with admixture of 3-substituted triazoles [38]. Careful comparison of CH2 signals in 1H NMR of triazoles 3 and 4 with those of 1-substituted and 3-substituted isomers showed that CH2 signals of minor isomers 4a and 4o are in good agreement with CH2 signals of 1-alkyl triazole (Figure 1). CH2-signals of major isomers of 3a and 3o are downfield shifted and differ from the CH2 signals of 3-alykyl isomers. Hence, major isomers 3a and 3o are 2-substrituted derivatives. It should be noted that substitution at the position 2 in NH-triazoles 1 is favored by both steric and electronic factors. Indeed, positions N-1 and N-3 of triazoles 1 are hindered by the bulky aryl substituent at C-5 and trifluoroacetyl group at C-4 atom of the triazole ring. As a result, the 2-isomer is a major one. In addition, the nucleophilicity of N-3 is diminished by the high electronegativity of the trifluoroacetyl group, which is why 3-N-isomers are not formed at all. It should be noted that major isomer 3 can be easily separated from isomer 4 by column chromatography on silica gel.
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 (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).
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.
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.

3. Materials and Methods

In general, 1H, 13C and 19F 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 1H and 1.30, 77.0 for 13C) as internal reference. The 19F 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 19F NMR using PhCF3 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), Na2CO3 (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 CH2Cl2 (3 × 10 mL); the organic phase was washed with water (2 × 10 mL), brine (10 mL) and dried over Na2SO4. Volatiles were evaporated in vacuo; the residue formed was purified by column chromatography on silica gel using gradient eluation by hexane-CH2Cl2 mixture (3:1) followed by hexane-CH2Cl2 mixture (1:1) and CH2Cl2. 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 1H NMR and 19NMR were measured for 3. Only the most characteristic signals of 3 are given in 13C NMR.
  • 1-(2-Benzyl-5-phenyl-2H-1,2,3-triazol-4-yl)-2,2,2-trifluoroethanone (3a). This was obtained from 1a (120 mg, 0.498 mmol) and benzyl bromide (94 mg, 0.550 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3a + 4a) was 139 mg (84%), ratio 3a:4a = 83:17. For pure 3a, it was beige oil, yield 115 mg (70%). 1H NMR (CDCl3, 400.1 MHz) was δ 7.96–7.86 (m, 2H), 7.53–7.44 (m, 5H), 7.44–7.36(m, 3H), 5.71 (s, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz) was δ 174.2 (q, 2JCF = 37.0 Hz), 152.7, 136.4, 133.5, 130.1, 129.1, 129.0, 128.9, 128.40, 128.35, 128.2, 116.3 (q, 1JCF = 290.7 Hz), 59.9. 19F NMR (CDCl3, 376.5 MHz): δ -74.9 (s, 3F). HRMS (ESI-TOF) was m/z [M + H]+. Calcd for C17H13F3N3O+ was 332.1005 and found: 332.1005. IR (ν, cm−1) was 1723 (C=O).
  • 1-(1-Benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-2,2,2-trifluoroethanone (4a). This was obtained from 1a as an admixture (83:17) in the synthesis of 3a. For pure 4a, see the following: Beige thick oil, yield 24 mg (14%). 1H NMR (CDCl3, 400.1 MHz): δ 7.58–7.52 (m, 1H), 7.51–7.46 (m, 2H), 7.31–7.25 (m, 3H), 7.24–7.20 (m, 2H), 7.08–7.00 (m, 2H), 5.46 (s, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.2 (q, 2JCF = 37.3 Hz), 143.9, 138.1, 133.9, 130.9, 129.4, 129.0, 128.9, 128.7, 127.7, 124.4, 116.1 (q, 1JCF = 290.6 Hz), 52.2. 19F NMR (CDCl3, 376.5 MHz): δ -75.4 (s, 3F). NMR data are in agreement with those in the literature [38].
  • 1-(2-Benzyl-5-(4-methoxyphenyl)-2H-1,2,3-triazol-4-yl)-2,2,2-trifluoroethanone (3b). This was obtained from 1b (62 mg, 0.229 mmol) and benzyl bromide (43 mg, 0.251 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3b + 4b) was 77 mg (93%), ratio 3b:4b = 81:19. For pure 3b, see the following: White solid, yield 0.0624 g (75.3%). 1H NMR (CDCl3, 400.1 MHz): δ 7.89 (d, 2H, 3J = 8.9 Hz), 7.48–7.33 (m, 5H), 6.97 (d, 2H, 3J = 8.9 Hz), 5.68 (s, 2H), 3.85 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.3 (q, 2JCF = 37.0 Hz), 161.0, 152.7, 136.1, 133.6, 130.6, 128.94, 128.89, 128.4, 120.6, 116.3 (q, 1JCF = 290.8 Hz), 113.8, 59.8, 55.3. 19F NMR (CDCl3, 376.5 MHz): δ −74.8 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C18H15F3N3O2+: 362.1111; found: 362.1089.
  • 1-(1-Benzyl-5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-2,2,2-trifluoroethanone (4b). This was obtained from 1b as an admixture (81:19) in the synthesis of 3b: colorless oil, yield 14.6 mg (17.3%). 1H NMR (CDCl3, 400.1 MHz): δ 7.33–7.27 (m, 3H), 7.17 (d, 2H, 3J = 8.7 Hz), 7.13–7.04 (m, 2H), 6.98 (d, 2H, 3J = 8.7 Hz), 5.47 (s, 2H), 3.87 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.2 (q, 2JCF = 37.1 Hz), 161.5, 144.0, 137.9, 134.1, 131.1, 129.0, 128.7, 127.6, 116.0, 116.2 (q, 1JCF = 290.8 Hz), 114.4, 55.4, 52.0. 19F NMR (CDCl3, 376.5 MHz): δ −75.2 (s, 3F).
  • 2,2,2-Trifluoro-1-(2-(4-nitrobenzyl)-5-phenyl-2H-1,2,3-triazol-4-yl)ethanone (3c). This was obtained from 1a (48 mg, 0.199 mmol) and 1-(bromomethyl)-4-nitrobenzene (47 mg, 0.218 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3c + 4c) was 0.0609 g (81%), ratio 3c:4c = 83:17. For pure 3c, see the following: beige solid, m.p. 97–101 °C, yield 0.0493 g (65.6%). 1H NMR (CDCl3, 400.1 MHz): δ 8.25 (d, 2H, 3J = 8.7 Hz), 7.91–7.82 (m, 2H), 7.60 (d, 2H, 3J = 8.7 Hz), 7.49–7.43 (m, 3H), 5.81 (s, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.1 (q, 2JCF = 37.7 Hz), 153.1, 148.3, 140.1, 136.9, 130.4, 129.3, 129.1, 128.5, 127.8,124.3, 116.1 (q, 1JCF = 290.6 Hz), 58.8. 19F NMR (CDCl3, 376.5 MHz): δ −75.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C17H12F3N4O3+: 377.0856; found: 377.0854.
  • 2,2,2-Trifluoro-1-(1-(4-nitrobenzyl)-5-phenyl-1H-1,2,3-triazol-4-yl)ethanone (4c). This was obtained from 1a as an admixture (81:19) in the synthesis of 3c: pale brown viscous mass, yield 11.6 mg (15.4%). 1H NMR (CDCl3, 400.1 MHz): δ 5.58 (s, 2H). 19F NMR (CDCl3, 376.5 MHz): δ -75.4 (s, 3F).
  • 1-(2-Allyl-5-phenyl-2H-1,2,3-triazol-4-yl)-2,2,2-trifluoroethanone (3d). This was obtained from 1a (50.2 mg, 0.208 mmol) and 3-chloroprop-1-ene (21 mg, 0.276 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3d + 4d) was 46 mg (79 %), ratio 3d:4d = 86:14. For pure 3d, see the following: colorless oil, yield 39.6 mg (68%). 1H NMR (CDCl3, 400.1 MHz): δ 7.93–7.84 (m, 2H), 7.50–7.43 (m, 3H), 6.21–6.09 (m, 1H), 5.45–5.37 (m, 2H), 5.16 (dt, 2H, 3J = 6.3 Hz, 4J = 1.4 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.3 (q, 2JCF = 37.0 Hz), 152.6, 136.4, 130.1, 130.0, 129.1, 128.4, 128.2, 120.9, 116.2 (q, 1JCF = 290.6 Hz), 58.5. 19F NMR (CDCl3, 376.5 MHz): δ −75.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C13H11F3N3O+: 282.0849; found: 282.0853.
  • 1-(1-Allyl-5-phenyl-1H-1,2,3-triazol-4-yl)2,2,2-trifluoroethanone (4d). This was obtained from 1a as an admixture (86:14) in the synthesis of 3d: colorless oil, yield 6.4 mg (11%). 1H NMR (CDCl3, 400.1 MHz): δ 7.58–7.50 (m, 3H), 7.40–7.36 (m, 2H), 5.95 (ddt, 1H, 2J = 16.9 Hz, 3J = 10.4 Hz, 3J = 5.7 Hz), 5.29 (d, 1H, 3J = 10.3 Hz), 5.06 (pseudo-dt, 1H, 2J = 17.1 Hz, 4J = 1.3 Hz), 4.89 (dt, 3J = 5.7 Hz, 4J = 1.5 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −75.3 (s, 3F).
  • 2,2,2-Trifluoro-1-(2-methyl-5-phenyl-2H-1,2,3-triazol-4-yl)ethanone (3e). This was obtained from 1a (51.9 mg, 0.215 mmol) and iodomethane (34 mg, 0.239 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3e + 4e) was 47.2 mg (86%), ratio 3e:4e = 83:17. For pure 3e, see the following: beige oil, yield 39.2 mg (71.4%). 1H NMR (CDCl3, 400.1 MHz): δ 7.92–7.84 (m, 2H), 7.50–7.44 (m, 3H), 4.35 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.1 (q, 2JCF = 37.0 Hz), 152.6, 136.3, 130.1, 129.0, 128.4, 128.2, 116.2 (q, 1JCF = 290.5 Hz), 42.8. 19F NMR (CDCl3, 376.5 MHz): δ −75.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C11H9F3N3O+: 256.0692; found: 256.0692.
  • 2,2,2-Trifluoro-1-(1-methyl-5-phenyl-1H-1,2,3-triazol-4-yl)ethanone (4e). This was obtained from 1a as an admixture (83:17) in the synthesis of 3e: beige oil, yield 8 mg (14.6%). 1H NMR (CDCl3, 400.1 MHz): δ 7.63–7.51 (m, 3H), 7.44–7.34 (m, 2H), 4.01 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 131.0, 129.4, 129.1, 35.5. 19F NMR (CDCl3, 376.5 MHz): δ −75.3 (s, 3F).
  • 1-(2-Ethyl-5-phenyl-2H-1,2,3-triazol-4-yl)-2,2,2-trifluoroethanone (3f). This was obtained from 1a (50.7 mg, 0.210 mmol) and bromoethane (25.5 mg, 0.234 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3f + 4f) was 0.052 g (92%), ratio 3f:4f = 91:9. For pure 3f, see the following: colorless oil, yield 47.2 mg (83.7%). 1H NMR (CDCl3, 400.1 MHz): δ 8.00–7.80 (m, 2H), 7.54–7.41 (m, 3H), 4.61 (q, 2H, 3J = 7.4 Hz), 1.68 (t, 3H, 3J = 7.4 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.2 (q, 2JCF = 36.7 Hz), 152.4, 136.1, 130.0, 129.0, 128.4, 116.3 (q, 1JCF = 290.7 Hz), 51.4, 14.5. 19F NMR (CDCl3, 376.5 MHz): δ −75.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C12H11F3N3O+: 270.0851; found: 270.0851.
  • 1-(1-Ethyl-5-phenyl-1H-1,2,3-triazol-4-yl)-2,2,2-trifluoroethanone (4f). This was obtained from 1a as an admixture (91:9) in the synthesis of 3f: colorless oil, yield 4.7 mg (8.3%). 1H NMR (CDCl3, 400.1 MHz): δ 7.61–7.52 (m, 3H), 7.39–7.36 (m, 2H), 4.33 (q, 2H, 3J = 7.3 Hz), 1.48 (t, 3H, 3J = 7.3 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −75.3 (s, 3F).
  • 2,2,2-Trifluoro-1-(5-phenyl-2-propyl-2H-1,2,3-triazol-4-yl)ethanone (3g). This was obtained from 1a (53.8 mg, 0.223 mmol) and bromopropane (30.3 mg, 0.246 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3g + 4g) was 58.7 mg (93%), ratio 3g:4g = 92:8. For pure 3g, see the following: beige oil, yield 54 mg (85.6%). 1H NMR (CDCl3, 400.1 MHz): δ 7.95–7.83 (m, 2H), 7.53–7.43 (m, 3H), 4.52 (t, 2H, 3J = 7.1 Hz), 2.10 (h (sextet), 2H, 3J = 7.3 Hz), 1.02 (t, 3H, 3J = 7.4 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.3 (q, 2JCF = 37.0 Hz), 152.3, 136.1, 130.0, 129.0, 128.42, 128.41, 116.3 (q, 1JCF = 290.8 Hz), 57.8, 22.9, 10.9. 19F NMR (CDCl3, 376.5 MHz): δ −75.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C13H13F3N3O+: 284.1005; found: 284.1007.
  • 2,2,2-Trifluoro-1-(5-phenyl-1-propyl-1H-1,2,3-triazol-4-yl)ethanone (4g). this was obtained from 1a as an admixture (92:8) in the synthesis of 3g: yield 4.7 mg (7.4%). 1H NMR (CDCl3, 400.1 MHz): δ 7.60–7.52 (m, 3H), 7.36 (dd, 2H, 3J = 7.5 Hz, 4J = 1.6 Hz), 4.24 (t, 2H, 3J = 7.3 Hz), 1.92–1.82 (m, 2H), 0.87 (t, 3H, 3J = 7.4 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.2 (q, 2JCF = 37.1 Hz), 143.7, 137.9, 130.8, 129.3, 129.1, 128.4, 116.2 (q, 1JCF = 289.3 Hz), 50.0, 29.7, 23.3. 19F NMR (CDCl3, 376.5 MHz): δ −75.3 (s, 3F).
  • 2,2,2-Trifluoro-1-(2-pentyl-5-phenyl-2H-1,2,3-triazol-4-yl)ethanone (3h). This was obtained from 1a (51.2 mg, 0.212 mmol) and bromopentane (35.6 mg, 0.236 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3h + 4h) was 58 mg (88 %), ratio 3h:4h = 92:8. For pure 3h, see the following: colorless oil, yield 53.4 mg (81%). 1H NMR (CDCl3, 400.1 MHz): δ 7.96–7.85 (m, 2H), 7.54–7.42 (m, 3H), 4.55 (t, 2H, 3J = 7.2 Hz), 2.13–2.01 (m, 2H), 1.46–1.30 (m, 4H), 0.96–0.88 (m, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.3 (q, 2JCF = 37.0 Hz), 152.3, 136.0, 130.0, 129.0, 128.4, 116.3 (q, 1JCF = 290.7 Hz), 56.2, 29.1, 28.4, 22.0, 13.8. 19F NMR (CDCl3, 376.5 MHz): δ −75.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C15H17F3N3O +: 312.1318; found: 312.1322.
  • 2,2,2-Trifluoro-1-(1-pentyl-5-phenyl-1H-1,2,3-triazol-4-yl)ethanone (4h). This was obtained from 1a as an admixture (92:8) in the synthesis of 3h: colorless oil, yield 4.6 mg (7%). 1H NMR (CDCl3, 400.1 MHz): δ 7.61–7.51 (m, 3H), 7.38–7.33 (m, 2H), 4.30–4.20 (m, 2H), 1.87–1.77 (m, 2H), 1.26–1.17 (m, 4H), 0.82 (t, 3H, 3J = 6.9 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 130.8, 129.3, 129.1, 124.8, 48.5, 29.6, 28.4, 21.9, 13.7. 19F NMR (CDCl3, 376.5 MHz): δ −75.3 (s, 3F). NMR data are in agreement with those in the literature [38].
  • 2,2,2-Trifluoro-1-(2-nonyl-5-phenyl-2H-1,2,3-triazol-4-yl)ethanone (3i). This was obtained from 1a (53.9 mg, 0.224 mmol) and bromononan (51.3 mg, 0.248 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3i + 4i) was 68.6 mg (83 %), ratio 3i:4i = 93:7. For pure 3i, see the following: colorless oil, yield 63.8 mg (77.2%). 1H NMR (CDCl3, 400.1 MHz): δ 7.94–7.85 (m, 2H), 7.50–7.43 (m, 3H), 4.55 (t, 2H, 3J = 7.2 Hz), 2.06 (p, 2H, 3J = 7.3 Hz), 1.44–1.21 (m, 12H), 0.91–0.83 (m, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.3 (q, 2JCF = 37.0 Hz), 152.3, 136.0, 130.0, 129.0, 128.42, 128.40, 116.3 (q, 1JCF = 290.7 Hz), 56.3, 31.8, 29.4, 29.3, 29.12, 28.9, 26.32, 22.61, 14.05. 19F NMR (CDCl3, 376.5 MHz): δ −75.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C19H25F3N3O+: 368.1944; found: 368.1950.
  • 2,2,2-Trifluoro-1-(1-nonyl-5-phenyl-1H-1,2,3-triazol-4-yl)ethanone (4i). This was obtained from 1a as an admixture (93:7) in the synthesis of 3i: Colorless oil, yield 4.8 mg (5.8%). 1H NMR (CDCl3, 400.1 MHz): δ 7.62–7.50 (m, 3H), 7.39–7.30 (m, 2H), 4.32–4.20 (m, 2H), 1.81 (p, 2H, 3J = 7.3 Hz), 1.32–1.13 (m, 12H), 0.86 (t, 3H, 3J = 7.0 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 130.8, 129.3, 129.1, 124.8, 48.5, 31.7, 29.9, 29.2, 29.08, 28.7, 26.27, 22.59, 14.06. 19F NMR (CDCl3, 376.5 MHz): δ −75.3 (s, 3F).
  • 2,2,2-Trifluoro-1-(2-phenethyl-5-phenyl-2H-1,2,3-triazol-4-yl)ethanone (3j). This was obtained from 1a (52.9 mg, 0.220 mmol) and (2-bromoethyl)benzene (44.8 mg, 0.242 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3j + 4j) was 64.8 mg (85 %), ratio 3j:4j = 93:7. For pure 3j, see the following: colorless oil, yield 60.3 mg (79%). 1H NMR (CDCl3, 400.1 MHz): δ 7.92–7.84 (m, 2H), 7.51–7.45 (m, 3H), 7.34–7.19 (m, 5H), 4.84–4.76 (m, 2H), 3.43–3.36 (m, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.2 (q, 2JCF = 37.2 Hz), 152.3, 136.5, 136.1, 130.1, 129.0, 128.8, 128.7, 128.4, 128.3, 127.1, 116.2 (q, 1JCF = 290.7 Hz), 57.2, 35.6. 19F NMR (CDCl3, 376.5 MHz): δ −75.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H3O]+ Calcd for C18H17F3N3O2+: 346.1267; found: 346.1270.
  • 2,2,2-Trifluoro-1-(1-phenethyl-5-phenyl-1H-1,2,3-triazol-4-yl)ethanone (4j). This was obtained from 1a as an admixture (93:7) in the synthesis of 3j: colorless oil, yield 4.5 mg (6%). 1H NMR (CDCl3, 400.1 MHz): δ 7.53–7.48 (m, 1H), 7.44–7.39 (m, 2H), 7.23–7.17 (m, 3H), 6.96–6.90 (m, 2H), 6.90–6.83 (m, 2H), 4.46 (t, 2H, 3J = 7.1 Hz), 3.19 (t, 2H, 3J = 7.1 Hz). 19F NMR (CDCl3, 376.5 MHz): δ -75.4 (s, 3F). NMR data are in agreement with those in the literature [38].
  • 2,2,2-Trifluoro-1-(2-isobutyl-5-phenyl-2H-1,2,3-triazol-4-yl)ethanone (3k). This was obtained from 1a (48.5 mg, 0.201 mmol) and 1-chloro-2-methylpropane (27.8 mg, 0.300 mmol) by heating for 14 h at 100 °C and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3k + 4k) was 50 mg (84%), ratio 3k:4k = 91:9. For pure 3k, see the following: colorless oil, yield 45.5 mg (76.2%). 1H NMR (CDCl3, 400.1 MHz): δ 7.95–7.82 (m, 2H), 7.53–7.42 (m, 3H), 4.37 (q, 2H, 3J = 7.3 Hz), 2.45 (hept, 1H, 3J = 6.9 Hz), 1.01 (s, 3H), 1.00 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.3 (q, 2JCF = 36.7 Hz), 152.2, 136.0, 130.0, 129.0, 128.41, 128.39, 116.3 (q, 1JCF = 290.7 Hz), 63.2, 29.4, 19.7. 19F NMR (CDCl3, 376.5 MHz): δ −75.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C14H15F3N3O+: 298.1163; found: 298.1163.
  • 2,2,2-Trifluoro-1-(1-isobutyl-5-phenyl-1H-1,2,3-triazol-4-yl)ethanone (4k). This was obtained from 1a as an admixture (91:9) in the synthesis of 3k: colorless oil, yield 4.5 mg (7.5%). 1H NMR (CDCl3, 400.1 MHz): δ 7.61–7.52 (m, 3H), 7.39–7.36 (m, 2H), 4.33 (q, 2H, 3J = 7.3 Hz), 1.48 (t, 3H, 3J = 7.3 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −75.3 (s, 3F).
  • 2,2,2-Trifluoro-1-(2-isopropyl-5-phenyl-2H-1,2,3-triazol-4-yl)ethanone (3l). This was obtained from 1a (49.8 mg, 0.207 mmol) and 1-bromo-2-methylpropane (29 mg, 0.238 mmol) by heating for 8 h at 80 °C and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3l + 4l) was 46 mg (79%), ratio 3l:4l = 94:6. For pure 3l, see the following: colorless oil, yield 43.2 mg (74.3%). 1H NMR (CDCl3, 400.1 MHz): δ 7.95–7.87 (m, 2H), 7.50–7.44 (m, 3H), 4.97 (hept, 1H, 3J = 6.7 Hz), 1.69 (s, 3H), 1.68 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.4 (q, 2JCF = 36.9 Hz), 152.0, 135.7, 130.0, 129.0, 128.6, 128.4, 116.3 (q, 1JCF = 290.9 Hz), 59.0, 22.1. 19F NMR (CDCl3, 376.5 MHz): δ −75.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C13H13F3N3O +: 284.1005; found: 284.1007.
  • 2,2,2-Trifluoro-1-(1-isopropyl-5-phenyl-1H-1,2,3-triazol-4-yl)ethanone (4l). This was obtained from 1a as an admixture (94:6) in the synthesis of 3l: colorless oil, yield 2.8 mg (4.7%). 1H NMR (CDCl3, 400.1 MHz): δ 7.60–7.52 (m, 3H), 7.36–7.31 (m, 2H), 4.54 (hept, 1H, 3J = 6.7 Hz), 1.61 (s, 3H), 1.59 (s, 3H). 19F NMR (CDCl3, 376.5 MHz): δ −75.3 (s, 3F).
  • 1-(2-Cyclohexyl-5-phenyl-2H-1,2,3-triazol-4-yl)-2,2,2-trifluoroethanone (3m). This was obtained from 1a (48 mg, 0.199 mmol) and bromocyclohexane (36 mg, 0.221 mmol) by heating for 14 h at 100 °C and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3m + 4m) was 45.1 mg (70%), ratio 3m:4m = 93:7. For pure 3m, see the following: white solid, m.p. 53–54 °C, yield 41.9 mg (65.1%). 1H NMR (CDCl3, 400.1 MHz): δ 7.97–7.82 (m, 2H), 7.52–7.40 (m, 3H), 4.68–4.50 (m, 1H), 2.34–2.23 (m, 2H), 2.06–1.90 (m, 4H), 1.80–1.72 (m, 1H), 1.54–1.28 (m, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.5 (q, 2JCF = 36.8 Hz), 151.9, 135.7, 129.9, 129.0, 128.7, 128.4, 116.5 (q, 1JCF = 290.9 Hz), 65.6, 32.4, 25.0, 24.8. 19F NMR (CDCl3, 376.5 MHz): δ −74.9 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C16H17F3N3O+: 324.1318; found: 324.1318.
  • 1-(1-Cyclohexyl-5-phenyl-1H-1,2,3-triazol-4-yl)2,2,2-trifluoroethanone (4m). This was obtained from 1a as an admixture (93:7) in the synthesis of 3m: yield 3.2 mg (4.9%). 1H NMR (CDCl3, 400.1 MHz): δ 7.82–7.68 (m, 2H), 7.48–7.32 (m, 3H), 5.06–4.96 (m, 1H), 2.34–2.17 (m, 2H), 2.06–1.90 (m, 4H), 1.80–1.72 (m, 1H), 1.54–1.28 (m, 3H). 19F NMR (CDCl3, 376.5 MHz): δ −75.3 (s, 3F).
  • 1,1′-(2,2′-(Butane-1,4-diyl)bis(5-phenyl-2H-1,2,3-triazole-4,2-diyl))bis(2,2,2-trifluoroethanone) (3n). This was obtained from 1a (74.1 mg, 0.307 mmol) and 1,4-dibromobytane (32.4 mg, 0.150 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3n + 4n) was 55 mg (67%), ratio 3n:4n = 83:17. For pure 3n, see the following: colorless oil, yield 45.7 mg (55.6%). 1H NMR (CDCl3, 400.1 MHz): δ 7.95–7.76 (m, 4H), 7.53–7.40 (m, 6H), 4.72–4.60 (m, 4H), 2.27–2.13 (m, 4H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.2 (q, 2JCF = 37.0 Hz), 152.5, 136.3, 130.2, 129.0, 128.5, 128.1, 116.2 (q, 1JCF = 290.8 Hz), 55.0, 26.1. 19F NMR (CDCl3, 376.5 MHz): δ −75.0 (s, 6F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C24H19F6N6O2+: 537.1468; found: 537.1467.
  • 2,2,2-Trifluoro-1-(5-phenyl-1-(4-(4-phenyl-5-(2,2,2-trifluoroacetyl)-2H-1,2,3-triazol-2-yl)butyl)-1H-1,2,3-triazol-4-yl)ethanone (4n). This was obtained from 1a as an admixture (83:17) in the synthesis of 3n: colorless oil, yield 9.4 mg (11.4%). 1H NMR (CDCl3, 400.1 MHz): δ 7.89–7.83 (m, 2H), 7.55–7.44 (m, 6H), 7.32 (dd, 2H, 3J = 7.9 Hz, 4J = 1.4 Hz), 4.53 (t, 2H, 3J = 6.6 Hz), 4.36 (t, 2H, 3J = 6.9 Hz), 2.09–2.01 (m, 2H), 1.99–1.86 (m, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.2 (q, 2JCF = 37.5 Hz), 174.1 (q, 2JCF = 37.7 Hz), 152.5, 143.7, 138.0, 136.3, 131.0, 130.3, 129.19, 129.16, 129.0, 128.5, 128.3, 128.0, 116.1 (q, 1JCF = 289.8 Hz), 116.1 (q, 1JCF = 291.0 Hz), 54.9, 47.5, 26.5, 26.0. 19F NMR (CDCl3, 376.5 MHz): δ −75.0 (s, 3F), −75.4 (s, 3F).
  • Ethyl 2-(4-phenyl-5-(2,2,2-trifluoroacetyl)-2H-1,2,3-triazol-2-yl)acetate (3o). this was obtained from 1a (52.9 mg, 0.219 mmol) and ethyl 2-bromoacetate (40.7 mg, 0.0244 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3o + 4o) was 57 mg (80%), ratio 3o:4o = 90:10. For pure 3o, see the following: Beige solid, m.p. 58–60 °C, yield 51.3 mg (72%). 1H NMR (CDCl3, 400.1 MHz): δ 7.93–7.84 (m, 2H), 7.50–7.44 (m, 3H), 5.34 (s, 2H), 4.29 (q, 2H, 3J = 7.1 Hz), 1.30 (t, 3H, 3J = 7.1 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.2 (q, 2JCF = 37.4 Hz), 165.3, 152.9, 137.1, 130,2, 129.1, 128.4, 127.9, 116.1 (q, 1JCF = 290.8 Hz), 62.6, 56.5, 14.0. 19F NMR (CDCl3, 376.5 MHz): δ −75.1 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C14H13F3N3O3+: 328.0904; found: 328.0908.
  • Ethyl 2-(5-phenyl-4-(2,2,2-trifluoroacetyl)-1H-1,2,3-triazol-1-yl)acetate (4o). This was obtained from 1a as an admixture (90:10) in the synthesis of 3o: colorless oil, yield 5.7 mg (8%). 1H NMR (CDCl3, 400.1 MHz): δ 7.56–7.52 (m, 2H), 7.38–7.36 (m, 2H), 5.04 (s, 2H), 4.21 (q, 2H, 3J = 7.1 Hz), 1.23 (t, 3H, 3J = 7.1 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 131.1, 129.2, 62.7, 49.1. 19F NMR (CDCl3, 376.5 MHz): δ −75.3 (s, 3F). NMR data are in agreement with those in the literature [38].
  • N,N-Dimethyl-2-(4-phenyl-5-(2,2,2-trifluoroacetyl)-2H-1,2,3-triazol-2-yl)acetamide (3p). This was obtained from 1a (47.6 mg, 0.198 mmol) and 2-chloro-N,N-dimethylacetamide (26.7 mg, 0.220 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2. Total yield (3p + 4p) was 52 mg (81%), ratio 3p:4p = 89:11. For the mixture of 3p and 4p, see the following: light yellow solid, m.p. 126–128 °C. For 3p: 1H NMR (CDCl3, 400.1 MHz): δ 7.92–7.84 (m, 2H), 7.47–7.41 (m, 3H), 5.43 (s, 2H), 3.08 (s, 3H), 3.00 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.2 (q, 2JCF = 37.2 Hz), 163.9, 152.8, 136.9, 130.1, 129.2, 128.3, 128.1, 116.2 (q, 1JCF = 291.0 Hz), 56.9, 36.4, 35.9. 19F NMR (CDCl3, 376.5 MHz): δ −74.9 (s, 3F). 1H NMR (CD3CN, 400.1 MHz): δ 7.88–7.80 (m, 2H), 7.56–7.46 (m, 3H), 5.54 (s, 2H), 3.03 (s, 3H), 3.00 (s, 3H). 13C{1H} NMR (CD3CN, 100.6 MHz): δ 174.8 (q, 2JCF = 36.5 Hz), 165.8, 153.2, 137.6, 131.0, 130.0, 129.4, 129.4, 117.2 (q, 1JCF = 290.2 Hz), 58.0, 38.4, 35.9. 19F NMR (CD3CN, 376.5 MHz): δ −73.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C14H14F3N4O2+: 327.1063; found: 327.1070.
  • N,N-Dimethyl-2-(5-phenyl-4-(2,2,2-trifluoroacetyl)-1H-1,2,3-triazol-1-yl)acetamide (4p). This was obtained from 1a as an admixture (89:11) in the synthesis of 3p: 1H NMR (CDCl3, 400.1 MHz): δ 7.55–7.47 (m, 3H), 5.08 (s, 2H), 2.97 (s, 3H), 2.95 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 130.9, 129.4, 128.9, 55.3. 19F NMR (CDCl3, 376.5 MHz): δ −75.3 (s, 3F). 1H NMR (CD3CN, 400.1 MHz): δ 5.21 (s, 2H). 13C{1H} NMR (CD3CN, 100.6 MHz): δ 131.8, 130.4, 129.7, 129.4, 117.2 (q, 1JCF = 290.2 Hz), 38.8, 36.9, 36.3. 19F NMR (CD3CN, 376.5 MHz): δ −73.2 (s, 3F).
  • 2,2,2-Trifluoro-1-(5-phenyl-2-tosyl-2H-1,2,3-triazol-4-yl)ethanone (3q). This was obtained from 1a (60 mg, 0.249 mmol) and 4-toluenesulfonyl chloride (52 mg, 0.274 mmol) and purified using gradient eluating by hexane-CH2Cl2 (1:1) followed by CH2Cl2: white crystals, m.p. 156–160 °C, yield 73 mg (74%). 1H NMR (CDCl3, 400.1 MHz): δ 8.08 (d, 2H, 3J = 8.4 Hz), 7.83 (dd, 2H, 3J = 7.9 Hz, 4J = 1.4 Hz) 7.52–7.39 (m, 5H), 2.46 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.5 (q, 2JCF = 37.9 Hz), 153.4, 148.1, 138.6, 131.6, 130.8, 130.6, 129.6, 129.3, 128.5, 126.9, 115.8 (q, 1JCF = 290.5 Hz), 21.9. 19F NMR (CDCl3, 376.5 MHz): δ −75.2 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C17H13F3N3O3S+: 396.0324; found: 396.0626. IR (ν, cm−1): 1731 (C=O).
  • 2,2,2-Trifluoro-1-(2-(methylsulfonyl)-5-phenyl-2H-1,2,3-triazol-4-yl)ethanone (3r). This was obtained from 1a (58.5 mg, 0.243 mmol) and methanesulfonyl chloride (30.5 mg, 0.267 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) and CH2Cl2: pale yellow solid, m.p. 99–100 °C, yield 62 mg (80%). 1H NMR (CDCl3, 400.1 MHz): δ 7.93–7.82 (m, 2H), 7.56–7.46 (m, 3H), 3.62 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.4 (q, 2JCF = 38.6 Hz), 153.6, 138.6, 131.1, 129.3, 128.7, 126.6, 115.8 (q, 1JCF = 290.4 Hz), 41.7. 19F NMR (CDCl3, 376.5 MHz): δ -75.2 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C11H9F3N3O3S +: 320.0313; found: 320.0315.
Synthesis of 2-aryltriazoles (5–11) by the reaction of triazoles (1) with aryl halogenides (general procedure). A 4 mL vial with a screw cap was charged with corresponding triazole 1 (0.5 mmol), DMF (1 mL), Na2CO3 (80 mg, 0.38 mmol, 1.5 equiv.) and corresponding aryl halogenide (0.55 mmol, 1.1 equiv.). The reaction mixture was stirred at room temperature for 1 day (for 5) or heated at 90–100 °C for 6–8 h until full consumption of the starting material (19F NMR control) occurred. The reaction mixture was broken by 0.1 M HCl (20 mL). The product was extracted by CH2Cl2 (3 × 10 mL); the organic phase was washed with water (2 × 10 mL), brine (10 mL) and dried over Na2SO4. Volatiles were evaporated in vacuo; the residue formed was purified by column chromatography on silica gel using gradient eluation by hexane-CH2Cl2 mixture (3:1) followed by hexane-CH2Cl2 mixture (1:1). Evaporation of the solvents afforded corresponding pure triazole 5–11.
  • 1-(2-(2,4-Dinitrophenyl)-5-phenyl-2H-1,2,3-triazol-4-yl)-2,2,2-trifluoroethanone (5). This was obtained from 1a (57 mg, 0.237 mmol) and 1-fluoro-2,4-dinitrobenzene (49 mg, 0.263 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1): pale yellow powder, m.p. 132–134 °C, yield 79 mg (82%). 1H NMR (CDCl3, 400.1 MHz): δ 8.67 (d, 1H, 4J = 2.4 Hz), 8.56 (dd, 1H, 3J = 8.9 Hz, 4J = 2.4 Hz), 8.31 (d, 1H, 3J = 8.9 Hz), 7.83 (dd, 2H, 3J = 7.7 Hz, 4J = 1.7 Hz), 7.49–7.40 (m, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 173.7 (q, 2JCF = 38.2 Hz), 153.8, 147.1, 142.8, 138.7, 134.1, 130.8, 129.0, 128.4, 127.4, 126.4, 120.7, 115.6 (q, 1JCF = 290.5 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −75.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C16H9F3N5O5+: 408.0550; found: 408.0549. IR (ν, cm−1): 1738 (C=O); 1545, 1540, 1349, 1335 (NO2).
  • 2,2,2-Trifluoro-1-(2-(4-nitrophenyl)-5-phenyl-2H-1,2,3-triazol-4-yl)ethanone (6). This was obtained from 1a (60 mg, 0.249 mmol) and 1-fluoro-4-nitrobenzene (44 mg, 0.312 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1): yellow solid, m.p. 166–168 °C, yield 59.1 mg (66%). 1H NMR (CDCl3, 400.1 MHz): δ 8.47–8.37 (m, 4H), 8.04–7.91 (m, 2H), 7.58–7.49 (m, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.3 (q, 2JCF = 37.8 Hz), 153.7, 147.7, 142.5, 138.3, 130.8, 129.2, 128.6, 127.3, 125.3, 120.2, 116.1 (q, 1JCF = 290.4 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −60.5 (s, 3F), −75.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C16H10F3N4O3+: 363.0700; found: 363.0704.
  • 2,2,2-Trifluoro-1-(2-(4-nitro-2-(trifluoromethyl)phenyl)-5-phenyl-2H-1,2,3-triazol-4-yl)ethanone (7). This was obtained from 1a (48.7 mg, 0.202 mmol) and 1-chloro-4-nitro-2-(trifluoromethyl)benzene (50.9 mg, 0.226 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1): light yellow solid, m.p. 109–111 °C, yield 46 mg (53%). 1H NMR (CDCl3, 400.1 MHz): δ 8.81 (d, 1H, 4J = 2.4 Hz), 8.62 (dd, 1H, 3J = 8.8 Hz, 4J = 2.5 Hz), 8.22 (d, 1H, 3J = 8.8 Hz), 8.02–7.94 (m, 2H), 7.56–7.49 (m, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.3 (q, 2JCF = 38.3 Hz), 153.7, 147.7, 140.8, 138.8, 130.9, 129.2, 128.7, 128.3, 127.9, 127.0, 126.2 (q, 2JCF = 35.1 Hz), 124.2 (q, 3JCF = 5.3 Hz), 121.5 (q, 1JCF = 274.4 Hz), 116.0 (q, 1JCF = 290.4 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −60.5 (s, 3F), −75.3 (s, 3F). HRMS (ESI-TOF): m/z [M + H3O]+ Calcd for C17H10F6N4O4+: 449.0679; found: 449.0675.
  • 2,2,2-Trifluoro-1-(2-(2-nitro-4-(trifluoromethyl)phenyl)-5-phenyl-2H-1,2,3-triazol-4-yl)ethanone (8). This was obtained from 1a (51 mg, 0.216 mmol) and 1-chloro-2-nitro-4-(trifluoromethyl)benzene (54 mg, 0.24 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1): pale yellow oil, yield 57 mg (62%). 1H NMR (CDCl3, 400.1 MHz): δ 8.27 (d, 1H, 3J = 8.5 Hz), 8.19 (pseudo-d, 1H, 4J = 1.1 Hz), 8.05 (dd, 1H, 3J = 8.5 Hz, 4J = 4.1 Hz), 7.97–7.88 (m, 2H), 7.57–7.46 (m, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.1 (q, 2JCF = 38.0 Hz), 153.9, 143.4, 138.8, 133.3, 132.7 (q, 2JCF = 35.0 Hz), 131.0, 129.9 (q, 3JCF = 3.5 Hz), 129.3, 128.7, 126.9, 126.1, 122.8 (q, 3JCF = 3.6 Hz), 122.2 (q, 1JCF = 273.3 Hz), 116.0 (q, 1JCF = 290.7 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −64.1 (s, 3F), −75.2 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C17H9F6N4O3+: 431.0573; found: 431.0576.
  • 2,2,2-Trifluoro-1-(2-(8-nitroquinolin-5-yl)-5-phenyl-2H-1,2,3-triazol-4-yl)ethanone (9). This was obtained from 1a (53.8 mg, 0.223 mmol) and 5-chloro-8-nitroquinoline (66 mg, 0.317 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1): yellow powder, m.p. 114–116 °C, yield 36 mg (39%). 1H NMR (CDCl3, 400.1 MHz): δ 9.09 (dd, 1H, 3J = 4.1 Hz, 4J = 1.6 Hz), 9.04 (dd, 1H, 3J = 8.9 Hz, 4J = 1.6 Hz), 8.49 (d, 1H, 3J = 8.3 Hz), 8.20 (d, 1H, 3J = 8.3 Hz), 8.03–7.95 (m, 2H), 7.76 (dd, 1H, 3J = 8.9 Hz, 4J = 4.1 Hz), 7.53–7.47 (m, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.5 (q, 2JCF = 37.5 Hz), 153.3, 152.8, 146.5, 142.5, 140.9, 138.3, 132.0, 130.4, 129.3, 128.5, 127.7, 125.5, 125.0, 123.6, 122.3, 121.2, 116.2 (q, 1JCF = 290.6 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −75.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C19H11F3N5O3+: 414.0809; found: 414.0809.
  • Ethyl 2,3,5,6-tetrafluoro-4-(4-phenyl-5-(2,2,2-trifluoroacetyl)-2H-1,2,3-triazol-2-yl)benzoate (10). This was obtained from 1a (58.5 mg, 0.243 mmol) and ethyl 2,3,4,5,6-pentafluorobenzoate (64 mg, 0.267 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1): pale yellow solid, m.p. 72–75 °C, yield 79.5 mg (71%). 1H NMR (CDCl3, 400.1 MHz): δ 7.98–7.85 (m, 2H), 7.57–7.47 (m, 3H), 4.51 (q, 2H, 3J = 7.2 Hz), 1.43 (t, 3H, 3J = 7.2 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.2 (q, 2JCF = 38.2 Hz), 158.4, 153.7, 145.1 (ddt, 2JCF = 255.2 Hz, 3JCF = 13.1 Hz, 4JCF = 5.4 Hz), 142.2 (ddd, 2JCF = 255.2 Hz, 3JCF = 15.6 Hz, 4JCF = 4.4 Hz), 138.9, 130.8, 129.3, 128.6, 126.9, 120.9 (tt, 3JCF = 12.7 Hz, 4JCF = 2.7 Hz), 116.0 (q, 1JCF = 290.6 Hz), 115.2 (t, 3JCF = 16.9 Hz), 63.4, 14.0. 19F NMR (CDCl3, 376.5 MHz): δ -75.2 (s, 3F), −138.13 – −138.23 (m, 2F), −145.58 – −145.74 (m, 2F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C19H11F7N3O3+: 462.0683; found: 462.0681.
  • 2,2,2-Trifluoro-1-(5-(4-methoxyphenyl)-2-(4-nitrophenyl)-2H-1,2,3-triazol-4-yl)ethanone (11). This was obtained from 1b (52 mg, 0.192 mmol) and 1-fluoro-4-nitrobenzene (30 mg, 0.213 mmol) and purified using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1): white solid, m.p. 55–57 °C, yield 47.7 mg (63%). 1H NMR (CDCl3, 400.1 MHz): δ 8.50–8.34 (m, 4H), 7.99 (d, 2H, 3J = 8.8 Hz), 7.02 (d, 2H, 3J = 8.8 Hz), 3.88 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.4 (q, 2JCF = 37.4 Hz), 161.7, 153.6, 147.7, 142.6, 138.1, 130.8, 125.3, 120.2, 119.7, 116.2 (q, 1JCF = 290.7 Hz), 114.1, 55.4. 19F NMR (CDCl3, 376.5 MHz): δ −74.8 (s, 3F). HRMS (ESI-TOF): m/z [M + H]− Calcd for C17H12F3N4O4−: 393.0816; found: 393.0822.
Synthesis of 2-aryltriazoles (12–20) by the reaction of triazoles (1) with boronic acids (general procedure).
A 30 mL vial was charged with corresponding triazole (1) (0.25 mmol), DMSO (1.5 mL), corresponding boronic acid (0.385 mmol, 1.5 equiv.) and Cu(OAc)2·H2O (5.1 mg, 0.257 mmol, 0.1 equiv.). The reaction mixture was heated at 90–100 °C for 8–10 h at open air using a magnetic stirrer with heating. The reaction mixture was poured into 0.1 M HCl (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic phase was washed with water (3 × 20 mL), dried over Na2SO4, and then volatiles were evaporated in vacuo. The residue was purified by column chromatography on silica gel using gradient eluating by hexane-CH2Cl2 (3:1) followed by hexane-CH2Cl2 (1:1) as eluents.
  • 1-(2,5-diPhenyl-2H-1,2,3-triazol-4-yl)-2,2,2-trifluoroethanone (12). This was obtained from triazole 1a (400 mg, 1.660 mmol) and PhB(OH)2 (309 mg, 2.553 mmol): colorless crystals, m.p. 93–95 °C yield 367 mg (77%). 1H NMR (CDCl3, 400.1 MHz): δ 8.28–8.18 (m, 2H), 8.03–7.95 (m, 2H), 7.59–7.46 (m, 6H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.4 (q, 2JCF = 37.5 Hz), 152.9, 138.8, 137.1, 130.4, 129.6, 129.4, 129.2, 128.5, 128.1, 119.7, 116.3 (q, 1JCF = 290.9 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −74.9 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C16H11F3N3O+: 318.0849; found: 318.0851. IR (ν, cm−1): 1716 (C=O).
  • 2,2,2-Trifluoro-1-(5-(4-methoxyphenyl)-2-phenyl-2H-1,2,3-triazol-4-yl)-ethanone (13). This was obtained from triazole 1b (77 mg, 0.284 mmol) and PhB(OH)2 (57 mg, 0.471 mmol): beige solid, m.p. 124–126 °C, yield 63 mg (64%). 1H NMR (CDCl3, 400.1 MHz): δ 8.28–8.15 (m, 2H), 8.02 (d, 2H, 3J = 9.0 Hz), 7.58–7.51 (m, 2H), 7.49–7.43 (m, 1H), 7.02 (d, 2H, 3J = 8.9 Hz), 3.87 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.4 (q, 2JCF = 37.1 Hz), 161.3, 152.8, 138.8, 136.8, 130.7, 129.5, 129.3, 120.4, 119.7, 116.4 (q, 1JCF = 290.9 Hz), 55.3. 19F NMR (CDCl3, 376.5 MHz): δ −74.7 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C17H13F3N3O2+: 348.0954; found: 348.0956.
  • 2,2,2-Trifluoro-1-(2-phenyl-5-(p-tolyl)-2H-1,2,3-triazol-4-yl)-ethanone (14). This was obtained from triazole 1c (95 mg, 0.373 mmol) and PhB(OH)2 (68 mg, 0.562 mmol): white solid, m.p. 124–126 °C, yield 109 mg (88%). 1H NMR (CDCl3, 400.1 MHz): δ 8.22 (d, 2H, 3J = 7.6 Hz), 7.93 (d, 2H, 3J = 8.2 Hz), 7.55 (t, 2H, 3J = 7.7 Hz), 7.47 (t, 1H, 3J = 7.3 Hz), 7.32 (d, 2H, 3J = 8.0 Hz), 2.44 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.4 (q, 2JCF = 37.2 Hz), 152.9, 140.6, 138.8, 137.0, 129.5, 129.3, 129.2, 129.1, 125.2, 119.6, 116.4 (q, 1JCF = 290.9 Hz), 21.4. 19F NMR (CDCl3, 376.5 MHz): δ -74.6 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C17H13F3N3O+: 332.1005; found: 332.1007.
  • 2,2,2-Trifluoro-1-(2-phenyl-5-(4-(trifluorometyl)phenyl)-2H-1,2,3-triazol-4-yl)-ethanone (15). This was obtained from triazole 1d (54 mg, 0.175 mmol) and PhB(OH)2 (31 mg, 0.256 mmol): white solid, m.p. 78–80 °C, yield 43 mg (64%). 1H NMR (CDCl3, 400.1 MHz): δ 8.22 (d, 2H, 3J = 7.8 Hz), 8.14 (d, 2H, 3J = 8.1 Hz), 7.77 (t, 2H, 3J = 8.1 Hz), 7.61–7.46 (m, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.5 (q, 2JCF = 37.8 Hz), 151.4, 138.6, 137.3, 132.1 (q, 2JCF = 32.9 Hz), 131.6, 129.72, 129.67, 129.6, 125.5 (q, 4JCF = 3.5 Hz), 123.8 (q, 1JCF = 272.4 Hz), 119.8, 116.2 (q, 1JCF = 290.6 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −64.1 (s, 3F), −74.6 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C17H10F6N3O+: 386.0723; found: 386.0737.
  • 2,2,2-Trifluoro-1-(2-(4-methoxyphenyl)-5-phenyl-2H-1,2,3-triazol-4-yl)-ethanone (16). This was obtained from triazole 1a (45 mg, 0.187 mmol) and (4-methoxyphenyl)boronic acid (51 mg, 0.338 mmol): white solid, m.p. 79–81 °C, yield 48 mg (74%). 1H NMR (CDCl3, 400.1 MHz): δ 8.13 (d, 2H, 3J = 9.2 Hz), 8.03–7.96 (m, 2H), 7.53–7.47 (m, 3H), 7.03 (d, 2H, 3J = 9.2 Hz), 3.88 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.3 (q, 2JCF = 37.0 Hz), 160.4, 152.8, 136.7, 132.4, 130.3, 129.2, 128.4, 128.2, 121.2, 116.4 (q, 1JCF = 290.6 Hz), 114.6, 55.6. 19F NMR (CDCl3, 376.5 MHz): δ −74.8 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C17H13F3N3O2+: 348.0954; found: 348.0957.
  • 2,2,2-Trifluoro-1-(2-(4-(hexyloxy)phenyl)-5-phenyl-2H-1,2,3-triazol-4-yl)-ethanone (17). This was obtained from triazole 1a (53 mg, 0.220 mmol) and (4-(hexyloxy)phenyl)boronic acid (73 mg, 0.329 mmol): white solid, m.p. 67–69 °C, yield 63 mg (69%). 1H NMR (CDCl3, 400.1 MHz): δ 8.15–8.06 (m, 2H), 8.05–7.93 (m, 2H), 7.54–7.45 (m, 3H), 7.06–6.96 (m, 2H), 4.02 (t, 2H, 3J = 6.6 Hz), 1.86–1.76 (m, 2H), 1.53–1.44 (m, 2H), 1.40–1.31 (m, 4H), 0.92 (t, 3H, 3J = 7.0 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.3 (q, 2JCF = 37.1 Hz), 160.0, 152.8, 136.7, 132.2, 130.2, 129.2, 128.5, 128.2, 121.2, 116.4 (q, 1JCF = 291.0 Hz), 115.1, 68.5, 31.6, 29.1, 25.7, 22.6, 14.0. 19F NMR (CDCl3, 376.5 MHz): δ −74.9 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C22H23F3N3O2+: 418.1737; found: 418.1733.
  • 1-(2-(4-Chloro-3-fluorophenyl)-5-phenyl-2H-1,2,3-triazol-4-yl)-2,2,2-trifluoroethanone (18). This was obtained from triazole 1a (38 mg, 0.158 mmol) and (4-chloro-3-fluorophenyl)boronic acid (41 mg, 0.235 mmol): pale yellow solid, m.p. 110–113 °C, yield 44.3 mg (76%). 1H NMR (CDCl3, 400.1 MHz): δ 8.05 (dd, 1H, 3J = 9.3 Hz, 4J = 2.4 Hz), 8.02–7.94 (m, 3H), 7.58 (dd, 1H, 3J = 8.7 Hz, 3J = 7.6 Hz), 7.54–7.48 (m, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.2 (q, 2JCF = 37.5 Hz), 158.3 (d, 1JCF = 250.9 Hz), 153.3, 138.0 (d, 3JCF = 9.1 Hz), 137.6, 131.1 (d, 2JCF = 92.7 Hz), 129.2, 128.6, 127.6, 122.3 (d, 3JCF = 17.9 Hz), 116.2 (q, 1JCF = 291.2 Hz), 115.8 (d, 4JCF = 3.9 Hz), 108.6 (d, 3JCF = 26.9 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −75.0 (s, 3F), −112.2 (t, 1F, J = 8.4 Hz). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C16H9ClF4N3O+: 370.0365; found: 370.0366.
  • 2,2,2-Trifluoro-1-(5-phenyl-2-(p-tolyl)-2H-1,2,3-triazol-4-yl)-ethanone (19). This was obtained from triazole 1a (36 mg, 0.149 mmol) and p-tolylboronic acid (30 mg, 0.221 mmol): white solid, m.p. 112–115 °C, yield 44 mg (89%). 1H NMR (CDCl3, 400.1 MHz): δ 8.13–8.06 (m, 2H), 8.05–7.96 (m, 2H), 7.55–7.47 (m, 3H), 7.34 (d, 2H, 3J = 8.2 Hz), 2.44 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.4 (q, 2JCF = 37.4 Hz), 152.8, 139.7, 136.9, 136.6, 130.3, 130.1, 129.2, 128.5, 128.2, 119.6, 116.3 (q, 1JCF = 290.5 Hz), 21.2. 19F NMR (CDCl3, 376.5 MHz): δ −74.9 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C17H13F3N3O+: 332.1005; found: 332.1007.
  • 2,2,2-Trifluoro-1-(5-phenyl-2-(thiophen-3-yl)-2H-1,2,3-triazol-4-yl)-ethanone (20). This was obtained from 1a (43 mg, 0.178 mmol) and thiophen-3-ylboronic acid (34 mg, 0.266 mmol): colorless solid, m.p. 98–100 °C, yield 59 mg (57%). 1H NMR (CDCl3, 400.1 MHz): δ 8.03–7.92 (m, 3H), 7.75 (dd, 1H, 3J = 5.3 Hz, 4J = 1.4 Hz), 7.55–7.48 (m, 3H), 7.45 (dd, 2H, 3J = 5.3 Hz, 4J = 1.4 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 174.3 (q, 2JCF = 37.1 Hz), 152.8, 138.1, 136.6, 130.4, 129.2, 128.5, 127.9, 127.2, 120.6, 116.3 (q, 1JCF = 290.7 Hz), 115.6. 19F NMR (CDCl3, 376.5 MHz): δ −74.9 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C14H9F3N3OS+: 324.0413; found: 324.0413.
Synthesis of amides 21–24 (general procedure). A 4 mL vial with a screw cap was charged with 1-(2,5-diзhenyl-2H-1,2,3-triazol-4-yl)-2,2,2-trifluoroethanone (12), (50–59 mg, 0.158–0.186 mmol) and corresponding amine (190–230 mg, ~2.7 mmol, ~12 equiv.) The reaction mixture was heated for 8 h at 90 °C (for 21) or at 110 °C (for 22–24) using a magnetic stirrer with heating. The reaction mixture was transferred into a round-bottom 50 mL flask using CH2Cl2 (10–15 mL), and then volatiles were evaporated in vacuo. The residue was passed through a short silica gel pad using CH2Cl2 followed by CH2Cl2 -MeOH (100:1) as eluents. Evaporation of volatiles afforded corresponding pure amides 21–24.
  • (2,5-Diphenyl-2H-1,2,3-triazol-4-yl)(pyrrolidin-1-yl)methanone (21). This was obtained from 12 (58.6 mg, 0.185 mmol) and pyrrolidine (190 mg, 2.66 mmol) by heating at 90 °C for 8 h: white solid, m.p. 94–96 °C, yield 55 mg (94%). 1H NMR (CDCl3, 400.1 MHz): δ 8.14–8.11 (m, 2H), 7.96–7.93 (m, 2H), 7.50–7.34 (m, 6H), 3.71 (t, 2H, 3J = 6.9 Hz), 3.46 (t, 2H, 3J = 6.9 Hz), 1.97–1.82 (m, 4H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 161.5, 146.8, 141.1, 139.3, 129.5, 129.2, 129.0, 128.6, 127.8, 127.6, 118.9, 48.3, 46.2, 25.9, 24.2. HRMS (ESI-TOF): m/z [M + H]+ Calcd for C19H19N4O+: 319.1553; found: 319.1560.
  • (2,5-Diphenyl-2H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone (22). This was obtained from 12 (50 mg, 0.158 mmol) and piperidine (205 mg, 2.41 mmol) by heating at 110 °C for 8 h: beige viscous oil, yield 37.4 mg (71%). 1H NMR (CDCl3, 400.1 MHz): δ 8.16–8.11 (m, 2H), 7.93–7.85 (m, 2H), 7.52–7.34 (m, 6H), 3.87–3.73 (m, 2H), 3.32–3.21 (m, 2H), 1.71–1.57 (m, 4H), 1.39–1.31 (m, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 162.1, 146.1, 140.6, 139.4, 129.31, 129.26, 129.1, 128.8, 127.8, 127.3, 118.9, 48.2, 43.0, 26.1, 25.4, 24.4. HRMS (ESI-TOF): m/z [M + H]+ Calcd for C20H21N4O+: 333.1710; found: 333.1715.
  • (2,5-Diphenyl-2H-1,2,3-triazol-4-yl)(morpholino)methanone (23). This was obtained from 12 (50 mg, 0.158 mmol) and morpholine (220 mg, 2.53 mmol) by heating at 110 °C for 8 h: beige solid, m.p. 140–142 °C, yield 37 mg (70%). 1H NMR (CDCl3, 400.1 MHz): δ 8.17–8.08 (m, 2H), 7.91–7.80 (m, 2H), 7.55–7.33 (m, 6H), 3.91–3.82 (m, 2H), 3.80–3.73 (m, 2H), 3.50–3.43 (m, 2H), 3.42–3.34 (m, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 162.2, 146.8, 139.6, 139.3, 129.3, 129.1, 128.9, 128.0, 127.5, 119.0, 66.58, 66.54, 47.4, 42.5. HRMS (ESI-TOF): m/z [M + H]+ Calcd for C19H19N4O2+: 335.1503; found: 335.1506.
  • N-Hexyl-2,5-diphenyl-2H-1,2,3-triazole-4-carboxamide (24). This was obtained from 12 (53 mg, 0.167 mmol) and hexan-1-amine (240 mg, 2.38 mmol) by heating at 110 °C for 8 h: white solid, m.p. 86–88 °C, yield 25 mg (43%). 1H NMR (CDCl3, 400.1 MHz): δ 8.20–8.06 (m, 4H), 7.54–7.37 (m, 6H), 6.98 (t, 1H, 3J = 4.7 Hz), 3.46 (dd, 2H, 3J = 13.4 Hz, 3J = 7.1 Hz), 1.67–1.60 (m, 2H), 1.44–1.28 (m, 6H), 0.91–0.87 (m, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 160.4, 139.5, 139.2, 129.38, 129.35, 129.2, 128.3, 128.2, 119.1, 39.5, 31.5, 29.6, 26.7, 22.5, 14.0. HRMS (ESI-TOF): m/z [M + H]+ Calcd for C21H25N4O +: 349.2023; found: 349.2029.

4. 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 Na2CO3 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%.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28124822/s1, Copies of all 1H, 13C and 19F NMR spectra.

Author Contributions

Conceptualization, V.M.M.; methodology, V.M.M.; validation, V.M.M.; formal analysis, V.M.M.; investigation, V.M.M. and Z.A.S.; writing—original draft preparation, V.M.M.; writing—review and editing, V.M.M., Z.A.S. and V.G.N.; visualization, V.M.M.; supervision, V.M.M.; project administration, V.G.N.; funding acquisition, V.G.N. All authors have read and agreed to the published version of the manuscript.

Funding

The research was conducted in terms of the state contract of the chair of organic chemistry of the Moscow State University entitled “Synthesis and study of physical, chemical and biological properties of organic and organometallic compounds”—CITIC No—AAAA-A21-121012290046-4.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in Supplementary Materials.

Acknowledgments

The authors acknowledge partial support from M. V. Lomonosov Moscow State University Program of Development.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 3–24 are available from the authors.

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Molecules 28 04822 sch001 550
Scheme 1. Screening of the reaction conditions for alkylation of triazole 1a with benzyl bromide and chloride.
Scheme 1. Screening of the reaction conditions for alkylation of triazole 1a with benzyl bromide and chloride.
Molecules 28 04822 sch001
Molecules 28 04822 sch002 550
Scheme 2. Alkylation and sulfonylation of triazoles 1.
Scheme 2. Alkylation and sulfonylation of triazoles 1.
Molecules 28 04822 sch002
Molecules 28 04822 g001 550
Figure 1. Elucidation of the structure of regioisomers 3 and 4.
Figure 1. Elucidation of the structure of regioisomers 3 and 4.
Molecules 28 04822 g001
Molecules 28 04822 sch003 550
Scheme 3. Arylation of triazoles 1 with various aryl halides 5–11.
Scheme 3. Arylation of triazoles 1 with various aryl halides 5–11.
Molecules 28 04822 sch003
Molecules 28 04822 sch004 550
Scheme 4. Cham–Lam arylation of triazoles 1.
Scheme 4. Cham–Lam arylation of triazoles 1.
Molecules 28 04822 sch004
Molecules 28 04822 sch005 550
Scheme 5. Reactions of triazole 12 with secondary amines.
Scheme 5. Reactions of triazole 12 with secondary amines.
Molecules 28 04822 sch005
Molecules 28 04822 g002 550
Figure 2. (a) Absorption and (b) emission spectra of solutions of compounds 3 in methanol.
Figure 2. (a) Absorption and (b) emission spectra of solutions of compounds 3 in methanol.
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Molecules 28 04822 g003 550
Figure 3. (a) Absorption and (b) emission spectra of solutions of compounds 6–8,10,11 in methanol.
Figure 3. (a) Absorption and (b) emission spectra of solutions of compounds 6–8,10,11 in methanol.
Molecules 28 04822 g003
Molecules 28 04822 g004 550
Figure 4. (a) Absorption and (b) emission spectra of solutions of compounds 12–20 in methanol.
Figure 4. (a) Absorption and (b) emission spectra of solutions of compounds 12–20 in methanol.
Molecules 28 04822 g004
Molecules 28 04822 g005 550
Figure 5. (a) Absorption and (b) emission spectra of solutions of compounds 21–24 in methanol.
Figure 5. (a) Absorption and (b) emission spectra of solutions of compounds 21–24 in methanol.
Molecules 28 04822 g005
Table
Table 1. Photophysical data of compounds 3.
Table 1. Photophysical data of compounds 3.
Compd. λ m a x a b s ,   nm / v ~ m a x a b s , cm−1ε, L·mol−1·cm−1 λ m a x f l ,   nm / v ~ m a x f l , cm−1φ aΔνST, cm−1
3a234/42,73015,140298/33,5500.099180
3d232/43,10010,900297/33,6700.079430
3e232/43,10012,200297/33,6700.079430
3p231/43,29013,090298/33,5500.079740
3q224/44,64018,750303/33,0000.0311,640
3r230/43,47011,700299/33,4400.0310,030
a Quantum yield φ relative to 2-aminopyridine in 0.1 M H2SO4 (φ = 0.6).
Table
Table 2. Photophysical data of compounds 6–8, 10–20.
Table 2. Photophysical data of compounds 6–8, 10–20.
Compd. λ m a x a b s ,   nm / v ~ m a x a b s ,   cm −1 a ε, L·mol−1· cm−1 λ m a x f l ,   nm / v ~ m a x f l , cm−1φ bΔνST, cm−1
6222/45,040
316/31,640		11,370
17,880		 —
7227/44,050
305/32,780		14,800
12,120		 —
8278/35,97015,240 —
10221/45,240
271/36,900		18,020
17,600
408/24,500
0.04
12,400
11230/43,480
329/30,390		14,650
19,290		 —
12276/36,23017,420335/29,8500.526380
13241/41,490
283/35,330		13,560
19,660
364/27,470
0.41
7860
14279/35,84020,630339/29,4900.606350
15276/36,23020,120342/29,2400.656990
16287/34,84016,580366/27,3200.597520
17289/34,60021,450368/27,1800.607420
18291/34,36022,860338/29,5800.574780
19279/35,84022,370345/28,9800.606860
20226/44,240
278/35,970		14,620
19,300
347/28,810
0.23
7160
a For compounds with two absorption bands, the positions of both bands are given, b quantum yield φ relative to 2-aminopyridine in 0.1 M H2SO4 (φ = 0.6).
Table
Table 3. Photophysical data of compounds 21–24.
Table 3. Photophysical data of compounds 21–24.
Compd. λ m a x a b s ,   nm / v ~ m a x a b s , cm−1ε, L·mol−1· cm−1 λ m a x f l ,   nm / v ~ m a x f l , cm−1φ aΔνST, cm−1
21290/34,48029,740342/29,2400.035240
22290/34,48020,310342/29,2400.045240
23289/34,60021,450340/29,4100.025190
24286/34,96019,420345/28,9800.265980
a Quantum yield φ relative to 2-aminopyridine in 0.1 M H2SO4 (φ = 0.6).
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Muzalevskiy, V.M.; Sizova, Z.A.; Nenajdenko, V.G. Regioselective Synthesis of New Family of 2-Substituted 1,2,3-Triazoles and Study of Their Fluorescent Properties. Molecules 2023, 28, 4822. https://doi.org/10.3390/molecules28124822

AMA Style

Muzalevskiy VM, Sizova ZA, Nenajdenko VG. Regioselective Synthesis of New Family of 2-Substituted 1,2,3-Triazoles and Study of Their Fluorescent Properties. Molecules. 2023; 28(12):4822. https://doi.org/10.3390/molecules28124822

Chicago/Turabian Style

Muzalevskiy, Vasiliy M., Zoia A. Sizova, and Valentine G. Nenajdenko. 2023. "Regioselective Synthesis of New Family of 2-Substituted 1,2,3-Triazoles and Study of Their Fluorescent Properties" Molecules 28, no. 12: 4822. https://doi.org/10.3390/molecules28124822

APA Style

Muzalevskiy, V. M., Sizova, Z. A., & Nenajdenko, V. G. (2023). Regioselective Synthesis of New Family of 2-Substituted 1,2,3-Triazoles and Study of Their Fluorescent Properties. Molecules, 28(12), 4822. https://doi.org/10.3390/molecules28124822

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