Synthesis of Amino Acid-Derived 1,2,3-Triazoles: Development of a

Article Cite This: J. Org. Chem. 2018, 83, 1348−1357

pubs.acs.org/joc

Synthesis of Amino Acid-Derived 1,2,3-Triazoles: Development of a Nontrivial Fluorescent Sensor in Solution for the Enantioselective Sensing of a Carbohydrate and Bovine Serum Albumin Interaction Natalí P. Debia,† Maiara T. Saraiva,‡ Bruna S. Martins,† Roiney Beal,§ Paulo F. B. Gonçalves,*,§ Fabiano S. Rodembusch,*,∥ Diego Alves,*,‡ and Diogo S. Lüdtke*,† †

Instituto de Química, Universidade Federal do Rio Grande do Sul, UFRGS, Av. Bento Gonçalves 9500, Porto Alegre, RS 91501-970, Brazil ‡ LASOLCCQFA, Universidade Federal de PelotasUFPEL, Pelotas, RS 96010-610, Brazil § Grupo de Química Teórica e Computacional, Universidade Federal do Rio Grande do SulUFRGS, Porto Alegre, RS 90040-060, Brazil ∥ Grupo de Pesquisa em Fotoquímica Orgânica Aplicada, Universidade Federal do Rio Grande do Sul - UFRGS, Porto Alegre, RS 90040-060, Brazil S Supporting Information *

ABSTRACT: A series of amino acid-derived 1,2,3-triazoles presenting the amino acid and the aromatic moieties connected by a triazole-4carboxylate spacer is discussed in this work. These compounds were achieved in good yields by organocatalytic enamine−azide [3 + 2] cycloadditions. One of the molecules obtained, bearing a 7chloroquinoline moiety, was photoactive in the UV-violet region and was successfully employed as a probe for substrate-specific enantiomeric sensing using D-(−)-arabinose and L-(+)-arabinose. The potential application as a fluorescent probe to detect protein in phosphate buffer solution was also explored using as model bovine serum albumin (BSA). The studied compounds presented both suppression and association behavior in the presence of BSA. In addition, theoretical calculations were performed at levels ωB97XD/cc-pVDZ and PBE1PBE/6-311+G(d,p) together with the polarizable continuum model to understand the interaction of the molecules with the enantiomers.

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INTRODUCTION

dipolarophile partner in the 1,3-dipolar cycloadditions with organic azides. There remains, however, a need for an in-depth study on the synthesis of more highly functionalized and complex 1,2,3-triazoles from various combinations of substrates. On the other hand, the development of organic optical sensors for analytical purposes such as optical assays and chemical sensing probes, has been highlighted as a subject of general interest.30 These particular optical sensors must present a fluorophoric unit which is able to interact with matter or energy, causing a change that can be correlated to the identity and/or quantity of the analyte of interest. Finally, this response can be transmitted as an optical signal that can be measured.31 In fluorimetric titrations, changes on the intensity or even on the maxima location can be associated with specific interaction between the analyte and the fluorophore. Thus, the research and development of enantioselective fluorescent sensors for the enantiodiscrimination of chiral compounds has been increasing quickly.32 These optical sensors present potential application in

Heterocyclic compounds represent one of the most general structural units found in several natural and synthetic bioactive compounds.1,2 In this line, 1,2,3-triazoles are an interesting class of nitrogen-based heterocycles extensively studied and used in the discovery of drug candidates and in new materials.3 Several methodologies have been reported for the preparation of 1,2,3triazoles, especially via thermal4 or metal-catalyzed (Cu, Ru, Ag, and Ir) 1,3-dipolar cycloaddition reactions of azides with alkynes.5 However, considering the restricted applications of metal-based methodologies in biological studies in view of their eco-adverse effects,6−12 recent studies have been directed toward the development of metal-free methodologies for the synthesis of fully substituted 1,2,3-triazoles.13,14 Organocatalytic approaches employing carbonyl compounds have been reported to promote the synthesis of highly functionalized 1,2,3-triazoles in high yields and mild reaction conditions.15−17 A range of carbonyl compounds such as β-keto esters, β-keto amides, β-keto sulfones, and α-cyano ketones, among others, have been employed as starting material in these protocols.18−29 In these organocatalyzed [3 + 2] cycloaddition reactions, the generated enamines or enolates might act as the © 2018 American Chemical Society

Received: November 10, 2017 Published: January 9, 2018 1348

DOI: 10.1021/acs.joc.7b02852 J. Org. Chem. 2018, 83, 1348−1357

Article

The Journal of Organic Chemistry

With these compounds in hand, we started the optimization studies for the enamine-azide [3 + 2] cycloaddition reaction using L-proline-derived β-keto ester 1 and 4-methoxyphenyl azide (5) as the starting materials. The first attempt for the 1,2,3-triazole synthesis was performing the reaction using Et2NH as the catalyst in DMSO as the solvent at room temperature (Table 1, entry 1). Unfortunately, under these conditions, no product was formed (entry 1). Heating the reaction to 80 °C greatly improved the outcome, and the desired triazole product 6 was isolated in 80% yield (entry 2). Then, the performance of different secondary amines was evaluated as catalysts for this reaction (entries 3−7); however, none of them resulted in improved yields for product 6. In the absence of an amine, no reaction was observed. Once the best reaction conditions were established, the scope was expanded to the other β-keto esters prepared and different aryl azides (Scheme 3). Initially, β-keto ester 1 was used in combination with different aryl azides displaying substituents with different electronic properties. The corresponding triazole products 6−11 were isolated with yields ranging from 25 to 89%. It is worth mentioning that the reactions with 4nitrophenyl azide and 4-azido-7-chloroquinoline afforded the corresponding products 10 and 11 in 88 and 89% yield, respectively. On the other hand, the reaction with phenyl azide was sluggish, and the desired product 8 was isolated in only 25% yield. Moreover, we also changed the structure of the βketo ester partner, and compounds 2−4 were also used in the reaction with 5. The 1,2,3-triazoles 12, 13, and 14 were obtained in 64, 50, and 72% yields, respectively. Compound 15, bearing a free NH group, was also prepared in excellent yield by Boc-deprotection using trifluoroacetic acid in CH2Cl2, followed by neutralization of the resulting salt with K2CO3 (Scheme 4). Photophysics. The absorption spectra of the amino acidderived 1,2,3-triazoles (6, 7, and 10−15) are shown in Figure 1 using 1,4-dioxane and acetonitrile as solvents (10−5 M). The relevant data from UV−vis absorption spectroscopy are presented in Table 2. From the analysis of the UV−vis absorption curves, it can be observed that in general, the studied compounds present absorption maxima (λabs) below 250 nm. For compounds containing chromophoric groups different from the benzene and triazole rings such as the nitro group (10) or the quinoline unity (11 and 15), a shift to longer wavelengths (>250 nm) was observed, as expected. Additionally, a very small solvatochromic effect could be observed in the ground state for the amino acidderived 1,2,3-triazoles, indicating an almost absent intramolecular charge transfer state. It is worth mentioning that for compound 6, the difference on the λabs location in respect to the solvents 1,4-dioxane and acetonitrile (39 nm) is believed to be related to the compound planarity. In 1,4-dioxane, the quinoline and triazole moieties seem to present a higher planarity, allowing an extended conjugation and consequently a redshift absorption (260 nm). On the other hand, acetonitrile does not allow such stabilization, and only the absorption located at 229 nm was observed. To better characterize the photophysical behavior of the synthesized compounds, the Strickler−Berg relation (eq 1) was applied to relate the molar absorptivity coefficient ε (M−1· cm−1) and the strength ( fe) of a single electron oscillator:36

high sensitivity assays to determine the enantioselectivity of a real-time system.33 The enantioselective fluorescent sensors are designed to incorporate one or more interaction and/or response mechanisms with a chiral target.33 In this context, macrocycles and supramolecular oligomers/polymers which operate through supramolecular interactions have been reported.34 Another frequent structural motif encountered in enantioselective fluorescent sensors is the binaphthol system.35 Several BINOL-derived compounds have been reported, and in some cases, the dendrimeric shape is used for signal amplification or even a derivative containing terpyridine (BINOL-terpyridine) or bis-BINOL connected by a monoamine can be found.33 In this work, we report the results of our studies toward the synthesis of amino acid-derived 1,2,3-triazoles through a metalfree, organocatalyzed enamide-azide [3 + 2]-cycloaddition. In addition, the ground state of these compounds was investigated by UV−vis absorption spectroscopy (Scheme 1). Noteworthy, Scheme 1. This Work

one of the synthesized compounds bearing a 7-chloroquinolinederived fluorophoric moiety was successfully used as fluorescent probe to detect bovine serum albumin (BSA) in an aqueous solution. Additionally, these compounds were also used as probes for enantiomeric recognition of the carbohydrate arabinose. Theoretical calculations were performed to propose an interaction mechanism to better describe the observed excited state deactivation channel present in this compound and explain the observed enantiomeric discrimination.

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RESULTS AND DISCUSSION Synthesis. The investigation started by the synthesis of the required amino acid-derived β-keto esters 1−4. The N-Boc amino acid derivatives were reduced to the corresponding amino alcohols, followed by transesterification with t-butyl acetoacetate, in the presence of DMAP (Scheme 2), giving the desired products in good overall yields. Scheme 2. Synthesis of β-Keto Esters 1−4

fe ≈ 4.3x10−9 1349

∫ εd v ̅

(1) DOI: 10.1021/acs.joc.7b02852 J. Org. Chem. 2018, 83, 1348−1357

Article

The Journal of Organic Chemistry Table 1. Screening of Reaction Conditions for the Reaction of β-Keto Ester 1 and 4-methoxyphenyl azide (5)a

entry

catalyst (10 mol %)

temp (°C)

yield (%)b

1 2 3 4 5 6 7 8

Et2NH Et2NH L-proline pyrrolidine piperidine dibenzylamine morpholine

25 80 80 80 80 80 80 80

NR 80 32 42 69 33 36 NR

All reactions performed using 1.0 equiv of β-keto ester 1 and 2.5 equiv of 4-methoxyphenyl azide (5) under argon atmosphere. bIsolated yield. NR = no reaction. a

Scheme 3. Scope of the Reaction

Scheme 4. Deprotection of 11

strength fe is present in eq 2.36 In addition, the pure radiative lifetime τ0 is defined as 1/ke0.37

In this equation, the integral is related to the area under the absorption curve from a plot of the molar absorptivity coefficient ε (M−1·cm−1) against wavenumber v ̅ (cm−1) and fe can be defined as a quantity that measures the intensity or probability of an electronic transition that is induced by the interaction of electrons and matter with the electromagnetic field of a light wave.37 The theoretical relationship which allows the calculation of the rate constant ke0 from the oscillator

ke0 ≈ 2.88x10−9 v0̅ 2

∫ εd v ̅

(2)

The limit values to the molar absorptivity coefficient, as well as calculated radiative rate constant associated with an oscillator strength of unity corresponds to ε around 105 M−1·cm−1 and ke0 around 109 s−1. Spin and symmetry allowed electronic transitions ranging over 4 orders of magnitude to ε and ke0 1350


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fluorescence signals. In this way, the photophysical study in the excited state was performed for these compounds and is presented in Figure 2. The relevant data from this study are

Figure 1. UV−vis absorption spectra in solution of the amino acidderived 1,2,3-triazoles (6, 7, and 10−15) in 1,4-dioxane (left) and acetonitrile (right).

Table 2. Relevant Photophysical Data of the UV−Vis Spectra of the Amino Acid-Derived 1,2,3-Triazoles (6, 7, and 10− 15)a compound

solvent

λabs

ε

fe

ke0

τ0

6

1,4-dioxane acetonitrile 1,4-dioxane acetonitrile 1,4-dioxane acetonitrile 1,4-dioxane acetonitrile 1,4-dioxane acetonitrile 1,4-dioxane acetonitrile 1,4-dioxane acetonitrile 1,4-dioxane acetonitrile

268 229 228 223 268 267 286 285 230 230 230 229 230 229 283 281

1.52 1.62 2.78 1.29 0.96 0.94 0.78 0.48 5.44 3.35 3.23 2.36 2.75 1.95 1.38 0.53

0.29 0.49 0.78 0.38 0.28 0.27 0.23 0.14 0.98 0.53 0.89 0.82 0.74 0.60 0.42 0.16

2.77 6.29 10.1 5.25 2.62 2.56 1.88 1.15 12.4 5.53 11.3 10.5 9.36 7.67 3.56 1.43

3.61 1.59 0.99 1.91 3.82 3.90 5.31 8.67 0.81 1.81 0.89 0.95 1.07 1.30 2.81 6.97

7 10 11 12 13 14 15

Figure 2. Fluorescence emission spectra in solution of the amino acidderived 1,2,3-triazole 11 in (a) 1,4-dioxane and (b) acetonitrile. In panel c, compound 11 is in a 1,4-dioxane solution at different excitation wavelengths (350−375 nm) ([10−5 M] and excitation/ emission slits 5.0/5.0 nm). The asterisk indicates the Raman signal.

summarized in Table 2. It is worth mentioning that the fluorescence emission spectra were obtained using, in addition to the absorption maxima, additional excitation wavelengths. The presence of different fluorophoric groups allowed the obtaining of fluorescence emission spectra using different excitation radiations. A scanning in the excitation wavelengths allowed us to evaluate and discard the hypothesis of these compounds not obeying Kasha’s rule. The amino acid-derived 1,2,3-triazole 11 presents in both solvents an almost absent fluorescence emission under excitation below 250 nm. At the absorption maxima in 1,4dioxane (286 nm, Figure 2a), a low intense emission could be observed located in the UV region (330 nm). Once again, in acetonitrile at 285 nm, the fluorescence emission remains almost absent. It is worth mentioning that for both solvents, the excitation wavelength (λexc) scanning indicated that dye 11 presents higher emission intensity at λexc > 300 nm. Higher intensity values were obtained under excitation at 312 and 368 nm in 1,4-dioxane (Figure 2a) and acetonitrile (Figure 2b), ascribed to emissions in the UV (332 nm) and cyan (441 nm) regions. The dependence on the fluorescence maxima location with the excitation wavelength was also studied scanning from 350 to 375 nm (Figure 2c). The result shows that compound 11 respects Kasha’s rule of excitation wavelength independence of the emission spectrum. Although less intense, a similar behavior was observed for compound 15 in 1,4-dioxane (see Supporting Information). BSA Interaction Study. BSA is widely used to study protein morphology and drug delivery, presenting high affinity to bind and transport ligands to specific sites, mainly due to the

λabs is the absorption maxima (nm), ε is the molar absorptivity (104 M−1·cm−1), fe is the calculated oscillator strength, ke0 is the calculated radiative rate constant (108 s−1), and τ0 is the calculated pure radiative lifetime (in ns). a

starting at 102 M−1·cm−1 and 105 s−1, respectively.37 In this way, based on the data summarized in Table 2, all compounds present spin and symmetry and allowed electronic transitions, which could be related to 1π−π* transitions. Due to the structural rigidity present on the chromophores in these compounds, values close to unity were obtained for the oscillator strength. Furthermore, an almost constant radiative lifetime (τ0) was observed for each compound changing the solvent. However, different values were calculated for τ0 among the studied compounds, ranging from 0.81 to 5.31 ns or 0.95 to 8.67 ns in 1,4-dioxane or acetonitrile, respectively. Although these compounds present the similar chromophoric and fluorophoric structures, the amino-acid seems to play a significant role on the photophysics of these dyes. In this way, despite the different calculated values, these results are probably indicating that after the radiation absorption the amino acid-derived 1,2,3-triazoles are populating the same excited state. After a screening based on the fluorescence emission signal from each compound, we observed that those presenting the quinoline moiety (11 and 15) showed the stronger 1351


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emission intensity. This photophysical behavior can be related to a significant affinity of the studied compounds with the protein, indicating its potential application as optical probes for protein detection in solution. Enantiomers Identification in Solution. The amino acidderived 1,2,3-triazoles 11 and 15 were also studied for enantioselective sensing using D-(−)-arabinose and L-(+)-arabinose as models (Figures 4 and 5). Fluorimetric titrations were

presence of two structured and hydrophobic binding pockets in its structure.38−40 Compounds 11 and 15 were studied as fluorescent probes for protein detection in solution using BSA as the model system. The BSA association study was performed with different amounts of protein (0−12 μM in PBS buffer pH 7.2) added to a solution of dyes 11 or 15 (2 μM in acetonitrile). After each addition, UV−vis and fluorescence emission spectra (λexc= 310 nm, Exc/Em slits of 10.0/10.0 nm) were obtained. It can be observed that the increase in BSA raised the absorption intensity at 278 nm with absence of redshift of maxima absorption (data not shown, see Supporting Information). The fluorescence emission spectra of both compounds in the absence and presence of BSA are given in Figure 3. It can be

Figure 4. Fluorescence emission intensities of the 1,2,3-triazoles 11 (20 μM) (left) and 15 (28 μM) (right) relative to the added volume of the enantiomers. [D-(−)-arabinose: 1.53 mM] and [L-(+)-arabinose: 1.73 mM]. All experiments were performed in acetonitrile at 25 °C.

performed using 11 (20 μM in acetonitrile) and 15 (28 μM in acetonitrile) in the presence of different amounts of D(−)-arabinose (18−110 μM) or L-(+)-arabinose (21−125 μM) both in DMSO. After each addition, UV−vis and

Figure 3. Fluorescence emission spectra of the amino acid-derived 1,2,3-triazoles (a) 11 and (b) 15 at different BSA concentrations (0− 12 μM) in a dye concentration of 2 μM in acetonitrile. In panel c, the linear relation of fluorescence intensity vs BSA concentration (μM) is also depicted (blank: in absence of BSA).

observed an emission maxima independent of the BSA amount located at 345 nm, related to the fluorophores present in 11 and 15. No additional fluorescence emission was observed, indicating the absence of aggregates in solution in these compounds. Both compounds already present fluorescence emission in absence of BSA (blank). Additionally, a linear correlation was observed between the fluorescence intensity and protein concentration up to 1.2 μM of BSA, as follows: 11 (R2 = 0.9987) and 15 (R2 = 0.9992). The first addition of BSA (1 μM) increased the fluorescence emission around 2 times. After the last BSA addition (12 μM), the fluorescence increased more than 10 times, without any shift on the maxima location. These preliminary results can probably be related to a confinement effect, afforded by specific interaction between the studied dyes and BSA. It is reported in the literature that aromatic and heterocyclic structures were found to bind within hydrophobic sites of BSA in specific subdomains, so-called IIA and IIIA.39,41−43 This interaction increases the rigidity of the fluorophore, minimizing the nonradiative deactivation of the excited state and consequently increasing the fluorescence

Figure 5. Ratio of the fluorescence emission intensities of the 1,2,3triazoles 11 (20 μM in acetonitrile) (top) and 15 (28 μM in acetonitrile) (bottom) at different enantiomer concentrations (18− 110 μM for D-(−)-arabinose and 21−125 μM for L-(+)-arabinose, respectively). 1352


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The Journal of Organic Chemistry fluorescence emission spectra (λexc= 310 nm, Exc/Em slits of 5.0/10.0 nm) were obtained. It can be observed that both compounds have a different response to the presence of the arabinose enantiomers in solution, indicating that their excited states can be notably affected by the presence of these compounds (Figure 4). The Boc-protected 1,2,3-triazole 11 shows a more intense fluorescence signal after the addition of equal amounts of D(−)-arabinose, when compared to L-(+)-arabinose. A similar behavior can be observed for the deprotected compound 15, because a more intense fluorescence emission was observed upon addition of the D-(−)-arabinose in comparison with the opposite enantiomer. Despite the similar result, the Bocprotected 1,2,3-triazole 11 presents the greatest difference between the values of the fluorescence intensities, which might be ascribed as the result of different interactions in the excited state between this fluorophore and each enantiomer of the carbohydrate. It is worth mentioning that no significant change was observed in the UV−vis spectra, indicating that in the ground state, both compounds behave equally (see Supporting Information). After it was observed that 1,2,3-triazoles 11 and 15 interact differently with each enantiomer of arabinose, a plot of the relative fluorescence intensity (I0/I) of these fluorophores against the concentration of the enantiomers in acetonitrile was made (Figure 5). In this plot, the fall of the ratio of the fluorescence intensity is related to the interaction between the fluorophore and the enantiomer. For compound 11, the higher the concentration of the carbohydrate, the lower the I0/I ratio, and higher the difference between D-(−)-arabinose and L(+)-arabinose. On the other hand, despite the also lower relative fluorescence intensity, compound 15 presents closer values to the I0/I ratio if compared to those of 11. Phenomenologically, the results depicted in Figures 4 and 5 indicate that L-(+)-arabinose behaves as a fluorescence quencher, probably due to a higher interaction with the fluorophore 11. Due to this interaction, fluorophore 11 and L(+)-arabinose are in closer proximity, resulting in a better interaction and thus allowing a nonradiative excited state deactivation or perhaps, due to the fluorophore emission and enantiomer UV absorption spectra overlap, an energy transfer from the fluorophore to the L-(+)-arabinose.44 The fluorescent sensitivity (ID/I0 and IL/I0), as well as the enantioselectivity (ID−I0)/(IL−I0) were also obtained in the recognition of the arabinose enantiomers. The relevant data are summarized in Table 3. Despite the observed variation on the fluorescent sensitivity for each enantiomer upon the fluorophore 11 or 15, the differences between these values are lower than those already published for different enantiomers.33 However, it is worth pointing out that differently from other systems used in

enantiomeric recognition studies, in which acidic and basic moieties are present at the probe and analyte, neither our 1,2,3triazole-derived optical sensor nor arabinose bear such reactive functionalities. Therefore, the response obtained in our enantiomeric sensing experiment is a result of weaker interactions, mainly resulting from hydrogen bonds, and the enantioselectivity values are similar or even higher than those of some amino acid derivatives using different chiral optical sensors.33 Theoretical Calculations. DFT calculations were performed using the Gaussian 16 package45 to obtain additional information about the interaction between the amino acidderived 1,2,3-triazoles and both enantiomers of arabinose. Initially, a geometry optimization of 11 and 15 was performed at the PBE1PBE/6-311+G(d,p) level. The influence of the solvent acetonitrile was considered in these calculations using polarizable continuum model (PCM). The interaction between compound 11 with D-(−)-arabinose or L-(+)-arabinose (Figure 6) was performed at ωB97XD/cc-pVDZ level. The interaction

Figure 6. Interaction systems of 1,2,3-triazole 11 with D-(−)-arabinose (top) and L-(+)-arabinose (bottom).

between compound 15 with D-(−)-arabinose or L-(+)-arabinose (Figure 7) was performed at PBE1PBE/6-311+G(d,p). In both cases, the thermodynamically favored β-arabinopyranose46 form of the carbohydrate was used for the calculations. It can be observed that the main interaction of both sets of compounds is due to two hydrogen bonds occurring between the 1,2,3triazoles 11 and each of the enantiomers of arabinose. In this case, the ΔE values of 1,2,3-triazoles 11 with D-(−)-arabinose are shown to be 8.61 kcal·mol−1 less stable than with L(+)-arabinose. In the interaction between 11 and D-(−)-arabinose, the first hydrogen bond takes place between the H19 and O47 atoms in a distance of 1.90 Å and the second one between the H8 and O56 atoms in a distance of 1.77 Å (Figure 6 top). The angles between O−H−O in the hydrogen bonds are 164.19° for O18H19O47 and 164.19° for O7H8O56. The hydrogen bonds

Table 3. Fluorescent Sensitivity and Enantioselectivity of the 1,2,3-Triazoles 11 and 15 in the Recognition of 60 μL of D(−)-Arabinose [1.53 mM] and L-(+)-Arabinose [1.73 mM] fluorescent sensitivity

a

fluorophore

ID/I0

IL/I0

enantioselectivity (ID−I0)/(IL−I0)

11 15

1.23 1.29

1.09 1.12

2.64 (2.22)a 2.33 (1.25)a

Obtained using 180 μL of the respective enantiomers. 1353


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of these compounds by UV−vis absorption spectroscopy were performed. 1,2,3-Triazoles 11 and 15 bearing a 7-chloroquinoline-derived fluorophoric moiety were selected from these studies for further applications. Both molecules were studied to detect the presence of protein in solution, using BSA as a model. In this study, the increase in the fluorescence emission in the presence of BSA was related to a significant affinity of the studied compounds with the protein, indicating its potential application as an optical probe. Furthermore, N-Boc 1,2,3triazole 11 was successfully used for enantiomeric recognition of the carbohydrate arabinose. We showed that interaction of 11 with L-(+)-arabinose led to a stronger fluorescence quenching, indicating that a stronger interaction occurs with the (+)-enantiomer of the carbohydrate, in contrast to what was observed with the (−)-enantiomer. To better understand this behavior, computational studies were carried out and revealed that a stronger interaction through hydrogen bonds occurs between 11 and L-(+)-arabinose.

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EXPERIMENTAL SECTION

General Information. Air- and moisture-sensitive reactions were conducted in flame- or oven-dried glassware equipped with tightly fitted rubber septa and under a positive pressure of dry argon. Reagents and solvents were handled by using standard syringe techniques. Temperatures above room temperature were maintained by use of a mineral oil bath heated on a hot plate. Column chromatography was performed using silica gel (230−400 mesh) following the methods described by Still.47 TLC was performed using supported silica gel GF254, 0.25 mm thickness. For visualization, TLC plates were either placed under ultraviolet light or treated with acid vanillin followed by heating. NMR spectra were recorded either with a Varian 300 and 400 MHz or a Bruker 400 MHz instrument in CDCl3 solutions. Chemical shifts are reported in ppm, referenced to the solvent peak of residual CHCl3 or TMS as reference. The data are reported as follows: chemical shift (δ), multiplicity, coupling constant (J) in Hz, and integrated intensity. 13C NMR spectra were recorded at 75 and 100 MHz in CDCl3 solutions. Chemical shifts are reported in ppm, referenced to the solvent peak CDCl3. Abbreviations to denote the multiplicity of a particular signal are s (singlet), d (doublet), t (triplet), dd (double doublet), m (multiplet), q (quartet), and br (broad singlet). ESI-QTOF-MS measurements were performed in the positive ion mode (m/z 50−2000 range). IR spectra were obtained on an FTIR-ATR instrument (Bruker). Melting points were obtained on a Buchi M-565. Optical rotations were measured using a JASCO P-200 digital polarimeter using 10 cm cells and are reported as [α]20 D, concentration (g/100 mL), and solvent. Spectroscopic grade solvents were used in the photophysical study. The UV−vis absorption spectra in solution were acquired on a Shimadzu UV-2450 spectrophotometer, and the steady-state fluorescence spectra were measured on a Shimadzu spectrofluorometer model RF-5301PC. Procedure for the Synthesis of β-Ketoesters. To the reaction flask, under inert atmosphere, was added the appropriate amino alcohol (1 equiv, 1.70 mmol), DMAP (0.25 equiv, 0.42 mmol), and dry toluene (6 mL). Then, tert-butyl acetoacetate (1.2 equiv, 2.04 mmol) was slowly added. The reaction system was heated under reflux for 24 h. After this period, the mixture was washed with distilled water, sat. NH4Cl, and sat. NaCl. The combined organic extracts were dried with anhydrous MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography, typically eluting with a mixture of EtOAc:hexanes, 30:70. tert-Butyl (S)-2-(((3-Oxobutanoyl)oxy)methyl)pyrrolidine-1carboxylate (1). Yellow oil in 71% yield (1.460 g, 5.12 mmol). −1 [α]20 D −40 (c 0.75, CH2Cl2). IR (cm ): 2982, 1690, 1395, 1164, 1102. Keto−enol equilibrium detected. 1H NMR (CDCl3, 300 MHz): 12.02 (s, 0.1H), 4.99 (s, 0.1H), 4.33−3.90 (m, 3H), 3.48 (s, 2H), 3.42−3.29 (m, 2H), 2.28 (s, 3H), 1.93−1.78 (m, 4H), 1.47 (s, 9H). 13C NMR (CDCl3, 75 MHz): 199.6, 171.5, 166.1, 153.7, 153.4, 88.7, 78.7, 78.4,

Figure 7. Interaction systems of 15 with D-(−)-arabinose (top) and L(+)-arabinose (bottom).

between 11 and the L-(+)-arabinose, which have been shown to be more stable, are shorter than with the D-(−)-arabinose. The first hydrogen bond distance between the H19 and O47 atoms has 1.80 Å with an angle between the atoms O18H19O47 of 168.51°. The second hydrogen bond between the H8 and O56 atoms also has a length of 1.80 Å, and the angle between O7H8O56 is 159.64° (Figure 6, bottom). The interaction between 15 and each enantiomer of the carbohydrate was also studied for comparison (Figure 7). The results showed once again that the interaction between the 1,2,3-triazoles 15 and L-(+)-arabinose is stronger than that with D-(−)-arabinose, but in this case, by a lower value (4.16 kcal· mol−1). The first interaction between 15 with D-(−)-arabinose (Figure 7, top) presented only one hydrogen bond, which causes a decrease in the interaction energy in the system. This interaction takes place between the atoms H11 and O47 and has a distance of 1.86 Å with an angle between O10−H11−O47 of 171.99°. On the other hand, the interaction of 15 with the L(+)-arabinose occurs through two hydrogen bonds (Figure 7 bottom). The first one between the H20 and O48 atoms presents a distance of 1.86 Å and an angle between O19−H20−O48 of 178.52°. The second one is through H8 and N55 and shows a length of 1.81 Å with an angle between O7−H8−N55 of 168.61°. The calculations are in agreement with the experimental findings, in which the L-(+)-arabinose enantiomer has a greater interaction with the 1,2,3-triazoles 11 and 15. It is believed that for this reason the differences in the fluorescence intensities between the enantiomers were observed. In both cases, two hydrogen bonds were found between the 1,2,3-triazoles and the arabinose enantiomers, which on average have a smaller distance, thus increasing the interaction and decreasing the energy of the system.

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CONCLUSIONS In summary, we described the synthesis of amino acid-derived 1,2,3-triazoles through a metal-free, organocatalyzed enamideazide [3 + 2]-cycloaddition. Ground state photophysical studies 1354


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4.34 (m, 2H), 4.28−4.13 (m, 1H), 3.48−3.38 (m, 2H), 2.59 (s, 3H), 2.08−1.99 (m, 3H), 1.91−1.84 (m, 1H),1.50−145 (m, 9H). 13C NMR (CDCl3, 100 MHz): 161.5, 154.5, 154.4, 139.0, 138.8, 136.6, 136.4, 135.4, 130.1, 129.6, 125.3, 79.8, 79.3, 64.8, 55.5, 46.7, 46.4, 28.4, 24.0, 23.8, 22.9, 22.6, 10.0. HRMS-ESI calcd for [C20H26N4O4+H]+: 387.2032, found 387.2037. (S)-(1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)methyl 1-(4-Fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate (9). White solid in 38% yield (0.077 g, 0.19 mmol). Mp: 121−122 °C. [α]20 D −37 (c 0.50, CH2Cl2). IR (cm−1): 2973, 2873, 1717, 1677, 1401, 1102. 1H NMR (CDCl3, 400 MHz): 7.41−7.35 (m, 2H), 7.25−7.16 (m, 2H), 4.41 (dd, J = 3.6, 10.8 Hz, 1H), 4.31 (dd, J = 7.2, 10.8 Hz, 1H), 4.18− 4.07 (m, 1H), 3.92−3.27 (m, 2H), 2.50 (s, 3H), 2.01−1.90 (m, 3H), 1.86−1.77 (m, 1H), 1.40 (s, 9H). 13C NMR (CDCl3, 75 MHz): 163.1 (d, J = 249.0 Hz), 161.3, 154.4, 139.0, 136.4, 131.4 (d, J = 2.9 Hz), 127.3 (d, J = 8.9 Hz), 116.7 (d, J = 23.1 Hz), 79.7, 79.3, 64.8, 55.5, 46.6, 46.4, 28.4, 23.7, 22.8, 9.9. HRMS-ESI calcd for [C20H25FN4O4+H]+: 405.1938, found 405.1963. (S)-(1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)methyl 5-Methyl1-(4-nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (10). Yellow solid in 88% yield (0.190 g, 0.44 mmol). Mp: 148−150 °C. [α]20 D −38 (c 0.54, CH2Cl2). IR (cm−1): 3088, 2978, 2880, 1728, 1691, 1389, 1344, 1109. 1H NMR (CDCl3, 400 MHz): 8.48 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 4.55−4.44 (m, 1H), 4.42 (dd, J = 6.8, 10.8 Hz, 1H), 4.30−4.12 (m, 1H), 3.46−3.32 (m, 2H), 2.69 (s, 3H), 2.10− 1.96 (m, 3H), 1.92−1.84 (m, 1H), 1.52−1.43 (m, 9H). 13C NMR (CDCl3, 100 MHz): 160.9, 154.5, 154.2, 148.0, 140.1, 138.9, 138.8, 137.1, 136.9, 125.7, 125.0, 79.6, 79.2, 65.0, 55.4, 46.6, 46.4, 28.3, 23.6, 22.8, 10.1. HRMS-ESI calcd for [C20H25N5O6+H]+: 432.1883, found 432.1905. (S)-(1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)methyl 1-(7Chloroquinolin-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxylate (11). Yellow solid in 89% yield (0.211 g, 0.45 mmol). Mp: 71−73 °C. −1 [α]20 D −26 (c 0.58, CH2Cl2). IR (cm ): 2982, 2873, 1721, 1684, 1392, 1143, 1099. 1H NMR (CDCl3, 400 MHz): 9.14 (d, J = 4.0 Hz, 1H), 8.40 (br, 1H), 7.59 (dd, J = 2.0, 8.8 Hz, 1H), 7.48 (d, J = 4.0 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 4.50−4.32 (m, 2H), 4.26−4.07 (m, 1H), 3.42−3.27 (m, 2H), 2.45 (s, 3H), 2.07−1.93 (m, 3H), 1.88−1.81 (m, 1H),1.47−136 (m, 9H). 13C NMR (CDCl3, 100 MHz): 160.9, 154.5,154.3, 151.1, 149.5, 140.5, 140.4, 139.6, 139.5, 137.3, 136.6, 136.5, 129.9, 128.6, 123.6, 122.1, 118.8, 79.7, 79.3, 65.1, 55.4, 55.3, 46.6, 46.4, 28.3, 23.6, 22.8, 9.6. HRMS-ESI calcd for [C23H26ClN5O4+H]+: 472.1752, found 472.1739. (S)-2-((tert-Butoxycarbonyl)amino)-3-phenylpropyl 1-(4-Methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate (12). Brown oil in 64% yield (0.148 g, 0.32 mmol). [α]20 D −6 (c 0.98, CH2Cl2). IR (cm−1): 3353, 2976, 1708, 1514, 1253, 1161, 1109. 1H NMR (CDCl3, 300 MHz): 7.36 (d, J = 9.0 Hz, 2H), 7.32−7.19 (m, 5H), 7.07 (d, J = 9.0 Hz, 2H), 5.15 (d, J = 8.4 Hz, 1H), 4.37−4.30 (m, 2H), 4.30−4.21 (m, 1H), 3.89 (s, 3H), 3.02−2.83 (m, 2H), 2.56 (s, 3H), 1.39 (s, 9H). 13C NMR (CDCl3, 75 MHz): 161.4, 160.6, 155.2, 139.2, 137.2, 135.9, 129.2, 129.1, 128.4, 128.2, 127.9, 126.6, 126.4, 126.1, 114.6, 79.2, 65.3, 55.5, 50.7, 37.8, 28.2, 9.8. HRMS-ESI calcd for [C25H30N4O5+H]+: 467.2294, found 467.2269. (S)-2-((tert-Butoxycarbonyl)amino)-3-methylbutyl 1-(4-Methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate (13). Brown waxy solid in 50% yield (0.105 g, 0.25 mmol). [α]20 D −18 (c 0.94, CH2Cl2). IR (cm−1): 3370, 3080, 2965, 1693, 1513, 1243, 1106. 1 H NMR (CDCl3, 400 MHz): 7.34 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 4.86 (d, J = 9.6 Hz, 1H), 4.48 (dd, J = 6.0, 11.2 Hz, 1H), 4.37 (dd, J = 4.0, 11.2 Hz, 1H), 3.89 (s, 3H), 3.85−3.76 (m, 1H), 2.54 (s, 3H), 1.96−1.94 (m, 1H), 1.41 (s, 9H), 1.03−0.98 (m, 6H). 13C NMR (CDCl3, 100 MHz): 161.4, 160.5, 155.6, 138.9, 136.0, 127.9, 126.5, 114.6, 78.9, 65.0, 55.5, 54.6, 28.2, 28.1, 19.3, 18.3, 9.8. HRMS-ESI calcd for [C21H30N4O5+H]+: 419.2294, found 419.2293. (S)-2-((tert-Butoxycarbonyl)amino)propyl 1-(4-Methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate (14). Beige solid in 72% yield (0.140 g, 0.36 mmol). Mp: 91−92 °C. [α]20 D −19 (c 0.53, CH2Cl2). IR (cm−1): 3386, 2978, 1701, 1501, 1209, 1126, 1062. 1H NMR (CDCl3, 400 MHz): 7.35 (d, J = 8.9 Hz, 2H), 7.06 (d,

64.40, 54.9, 54.6, 49.1, 45.9, 45.7, 27.6, 22.9, 22.2, 20.3. HRMS-ESI calcd for [C14H23NO5+H]+: 286.1654, found 286.1656. (S)-2-((tert-Butoxycarbonyl)amino)-3-phenylpropyl 3-oxobutanoate (2). White solid in 95% yield (0.540 g, 1.61 mmol). −1 Mp: 65−66 °C. [α]20 D −14 (c 0.6, CH2Cl2). IR (cm ): 3383, 3023, 2979, 1734, 1686, 1518, 1160. Keto−enol equilibrium detected. 1H NMR (CDCl3, 400 MHz): 11.95 (s, 0.1H), 7.32−7.15 (m, 5H), 5.05 (s, 0.1H), 4.80−4.71 (m, 1H), 4.24−4.15 (m,1H), 4.12−4.01 (m, 2H), 3.51 (s, 2H), 2.88 (dd, J = 6.0, 13.6 Hz, 1H), 2.79 (dd, J = 7.6, 13.6 Hz, 1H), 2.29 (s, 3H), 1.41 (s, 9H).13C NMR (CDCl3, 100 MHz): 200.4, 166.8, 155.1, 137.0, 129.1, 128.4, 126.5, 89.3, 79.4, 65.5, 50.5, 49.8, 37.7, 28.2, 21.1. HRMS-ESI calcd for [C18H25NO5+H]+: 336.1811, found 336.1814. (S)-2-((tert-Butoxycarbonyl)amino)-3-methylbutyl 3-oxobutanoate (3). Pale yellow waxy solid in 98% yield (0.333 g, 1.16 −1 mmol). [α]20 D −29 (c 0.76, CH2Cl2). IR (cm ): 3370, 2976, 1744, 1686, 1524, 1242, 1143. Keto−enol equilibrium detected. 1H NMR (CDCl3, 300 MHz): 11.97 (s, 0.1H), 5.00 (s, 0.1H), 4.68−4.57 (m, 1H), 4.23 (dd, J = 4.2, 11.1 Hz, 1H), 4.16 (dd, J = 6.3, 11.1 Hz, 1H), 3.72−3.62 (m, 1H), 3.47 (s, 2H), 2.28 (s, 3H), 1.79 (m, 1H), 1.44 (s, 9H), 0.96 (d, J = 5.1 Hz, 3H), 0.94 (d, J = 5.1 Hz, 3H). 13C NMR (CDCl3, 75 MHz): 200.4, 166.9, 155.6, 89.4, 79.2, 65.4, 54.4, 49.8, 29.5, 28.2, 19.2, 18.2. HRMS-ESI calcd for [C14H25NO5+H]+: 288.1811, found 288.1809. (S)-2-((tert-Butoxycarbonyl)amino)propyl 3-oxobutanoate (4). White solid in 89% yield (0.3927 g, 1.51 mmol). Mp: 45−47 −1 °C. [α]20 D −19 (c 0.56, CH2Cl2). IR (cm ): 3372, 2983, 1731, 1686, 1525, 1160. Keto−enol equilibrium detected. 1H NMR (CDCl3, 400 MHz): 11.97 (s, 0.1H), 5.02 (s, 0.1H), 4.62 (br, 1H), 4.16 (dd, J = 4.4, 11.2 Hz, 1H), 4.08 (dd, J = 5.6 Hz, 11.2 Hz, 1H), 3.97 (br, 1H), 3.49 (s, 2H), 2.28 (s, 3H), 1.44 (s, 9H), 1.17 (d, J = 6.8 Hz, 3H). 13C NMR (CDCl3, 75 MHz): 200.4, 166.8, 155.0, 89.3, 79.2, 67.8, 66.5, 49.7, 45.1, 28.2, 21.0, 17.4. HRMS-ESI calcd for [C12H21NO5+H]+: 260.1498, found 260.1469. Procedure for the Synthesis of 1,4,5-Trisubstituted-1,2,3triazoles. To the reaction flask, under inert atmosphere, were added the aryl azide (2.5 equiv, 1.25 mmol) and the appropriate β-keto ester (1 equiv, 0.50 mmol) in dry DMSO (1 mL). Then, 10 mol % of the catalyst Et2NH (0.1 equiv, 0.05 mmol) was added, and the reaction mixture was stirred for 24 h at 80 °C. After reaction time, the solvent was removed in vacuum. The crude product was purified by flash column chromatography using an appropriate mixture of AcOEt/ hexane. (S)-(1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)methyl 1-(4-Methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate (6). Pale orange solid in 80% yield (0.166 g, 0.40 mmol). Mp: 77−79 −1 °C. [α]20 D −36 (c 0.55, CH2Cl2). IR (cm ): 3085, 2966, 1724, 1684, 1367, 1107. 1H NMR (CDCl3, 300 MHz): 7.36 (d, J = 9.0 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 4.58−4.08 (m, 3H), 3.89 (s, 3H), 3.50−3.27 (m, 2H), 2.55 (s, 3H), 2.10−1.96 (m, 3H), 1.94−1.79 (m, 1H), 1.53− 1.42 (m, 9H). 13C NMR (CDCl3, 100 MHz): 161.5, 160.6, 154.5, 154.4, 139.1, 139.0, 136.3, 136.2, 128.1, 126.7, 79.7, 79.3, 64.7, 55.6, 46.7, 46.4,28.8, 28.6, 28.4, 27.9, 23.7, 22.8, 9.9. HRMS-ESI calcd for [C21H28N4O5+H]+: 417.2138, found 417.2141. (S)-(1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)methyl 5-Methyl1-(p-tolyl)-1H-1,2,3-triazole-4-carboxylate (7). Beige solid in 52% yield (0.104 g, 0.26 mmol). Mp: 120−121 °C. [α]20 D −39 (c 0.50, CH2Cl2). IR (cm−1): 2975, 2918, 1714, 1684, 1399, 1106. 1H NMR (CDCl3, 400 MHz): 7.37 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 4.55−4.32 (m, 2H), 4.28−4.13 (m, 1H), 3.46−3.30 (m, 2H), 2.57 (s, 3H), 2.46 (s, 3H), 2.07−1.84 (m, 4H),1.51−1.43 (m, 9H).13C NMR (CDCl3, 100 MHz): 161.4, 154.4, 154.3, 140.3, 138.9, 138.8, 136.3, 136.2, 132.8, 130.1, 125.0, 79.7, 79.2, 64.7, 55.5, 46.7, 46.4,28.8, 28.4, 27.9,23.7, 22.8, 21.1, 9.9. HRMS-ESI calcd for [C21H28N4O4+H]+: 401.2189, found 401.2187. (S)-(1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)methyl 5-Methyl1-phenyl-1H-1,2,3-triazole-4-carboxylate (8). Pale yellow waxy solid in 25% yield (0.048 g, 0.12 mmol). [α]20 D −37 (c 0.34, CH2Cl2). IR (cm−1): 2975, 2952, 1718, 1677, 1399, 1166, 1102. 1H NMR (CDCl3, 400 MHz): 7.61−7.55 (m, 3H), 7.48−7.43 (m, 2H), 4.54− 1355


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The Journal of Organic Chemistry Notes

J = 8.9 Hz, 2H), 4.91−4.80 (m, 1H), 4.39 (dd, J = 5.2, 11.0 Hz, 1H), 4.34 (dd, J = 4.4, 11.0 Hz, 1H), 4.19−4.08 (m, 1H), 3.89 (s, 3H), 2.56 (s, 3H), 1.43 (s, 9H), 1.28 (d, J = 6.8 Hz, 3H). 13C NMR (CDCl3, 100 MHz): 161.5, 160.6, 155.1, 139.1, 136.0, 128.1, 126.6, 114.7, 79.3,67.5, 55.6, 45.4, 28.2, 17.7, 9.9. HRMS-ESI calcd for [C19H26N4O5+H]+: 391.1982, found 391.2007. Procedure for the Deprotection of the Boc-Group. To a solution of the 1,2,3-triazole 11 (1 equiv, 0.18 mmol, 0.085 g) in dichloromethane (0.36 mL), TFA (13 equiv, 2.34 mmol, 0.18 mL) was slowly added. The reaction mixture was stirred at room temperature for 2 h. Then, the volatile substances were evaporated. The residue was dissolved in dichloromethane, and the solvent was evaporated (this process was repeated three times). The result oil was dissolved in dichloromethane (0.36 mL), and K2CO3 (3.6 equiv, 0.65 mmol, 0.090 g) was added. The mixture was stirred at room temperature for 2 h. Then, the solids were separated by filtration, and the filtrate was evaporated. The crude product was purified by flash column chromatography using a mixture of AcOEt:Et3N (99:1). (S)-Pyrrolidin-2-ylmethyl 1-(7-Chloroquinolin-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxylate (15). Beige solid in 89% yield (0.060 g, 0.16 mmol). Mp: 171−173 °C. [α]20 D −41 (c 0.17, CH2Cl2). IR (cm−1): 3340, 2980, 2874, 1589, 1420, 1050. 1H NMR (CDCl3, 400 MHz): 9,15 (d, J = 4.8 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 2.0, 9.2 Hz, 1H), 7.43 (d, J = 4.4 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 4.91−4.84 (m, 1H), 4.57−4.49 (m, 1H), 4.48−4.39 (m, 1H), 4.17−4.08 (m, 1H), 3.86−3.76 (m, 2H), 2.46 (s, 3H), 2.22−2.13 (m, 1H), 2.09−1.92 (m, 2H), 1.79−1.70 (m, 1H). 13C NMR (CDCl3, 100 MHz): 162.8, 151.3, 150.0, 140.2, 140.0, 139.8, 137.2, 129.8, 129.1, 123.8, 122.3, 118.8, 67.2, 62.3, 50.4, 28.0, 25.0, 10.0. HRMS-ESI calcd for [C18H18ClN5O2+H]+: 372.1227, found 372.1222. BSA Association Study. A dye solution in acetonitrile (11: 2 μM and 15: 3 μM) was used to prepare a dye solution in PBS (12 μL in 3 mL of PBS). To this PBS/dye solution, different amounts of a previously prepared PBS/BSA solution (1−12 μM in PBS pH 7.2) were added. The final solution was kept to rest for 1 h. The fluorescence spectra were obtained at 25 °C and under excitation at 310 nm using Exc/Em slits of 10.0/10.0 nm, respectively. Enantiomer Interaction Study. To a solution of 11 (20 μM) or 15 (28 μL), both in acetonitrile, different amounts of DMSO solutions of D-(−)-arabinose (18−110 μM) and L-(+)-arabinose (21−125 μM) were added. In this study, the enantiomer concentrations correspond to the addition of 30−180 μL (in 30 μL step) of each enantiomer to the dye solution. The working concentrations of the enantiomers were 1.53 and 1.73 mM for D-(−)-arabinose and L-(+)-arabinose, respectively. This fluorimetric titration was performed using an excitation wavelength of 310 nm with Exc/Em slits of 5.0/10.0 nm, respectively. All experiments were performed at 25 °C.

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by CNPq, CAPES, and INCTCatálise. We also thank Andressa M. M. Carlos for assistance with HPLC analysis.

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(1) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; WileyVCH: Weinheim, 2003. (2) Katrizky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic Chemistry, 2nd ed.; Pergamon: Amsterdam, 2000. (3) For a recent set of reviews in this area, see the themed issue: Applications of click chemistry. Chem. Soc. Rev. 2010, 39, 1221.10.1039/c003926h (4) Huisgen, R. Angew. Chem. 1963, 75, 604. (5) For representative examples on metal-catalyzed 1,3-dipolar cycloaddition, see: (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. (c) Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Zhao, H.; Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 8923. (d) McNulty, J.; Keskar, K.; Vemula, R. Chem. - Eur. J. 2011, 17, 14727. (e) Ding, S.; Jia, G.; Sun, J. Angew. Chem., Int. Ed. 2014, 53, 1877. (6) Baskin, J. M.; Bertozzi, C. R. QSAR Comb. Sci. 2007, 26, 1211. (7) Jomova, K.; Valko, M. Toxicology 2011, 283, 65. (8) Gierlich, J.; Burley, G. A.; Gramlich, P. M. E.; Hammond, D. M.; Carell, T. Org. Lett. 2006, 8, 3639. (9) Lallana, E.; Fernandez-Megia, E.; Riguera, R. J. Am. Chem. Soc. 2009, 131, 5748. (10) Link, A. J.; Vink, M. K. S.; Tirrell, D. A. J. Am. Chem. Soc. 2004, 126, 10598. (11) Gaetke, L. M.; Chow, C. K. Toxicology 2003, 189, 147. (12) Kennedy, D. C.; McKay, C. S.; Legault, M. C. B.; Danielson, D. C.; Blake, J. A.; Pegoraro, A. F.; Stolow, A.; Mester, Z.; Pezacki, J. P. J. Am. Chem. Soc. 2011, 133, 17993. (13) Debets, M. F.; Van Berkel, S. S.; Dommerholt, J.; Dirks, A. J.; Rutjes, F. P. J. T.; Van Delft, F. L. Acc. Chem. Res. 2011, 44, 805. (14) Baskin, J. M.; Bertozzi, C. R. Aldrichimica Acta 2010, 43, 15. (15) Lima, C. G. S.; Ali, A.; Van Berkel, S. S.; Westermann, B.; Paixão, M. W. Chem. Commun. 2015, 51, 10784. (16) Ramasastry, S. S. V. Angew. Chem., Int. Ed. 2014, 53, 14310. (17) John, J.; Thomas, J.; Dehaen, W. Chem. Commun. 2015, 51, 10797. (18) Danence, L. J. T.; Gao, Y.; Li, M.; Huang, Y.; Wang, J. Chem. Eur. J. 2011, 17, 3584. (19) Belkheira, M.; El Abed, D.; Pons, J.-M.; Bressy, C. Chem. - Eur. J. 2011, 17, 12917. (20) Wang, L.; Peng, S.; Danence, L. T. T.; Gao, Y.; Wang, J. Chem. Eur. J. 2012, 18, 6088. (21) Yeung, D. K. J.; Gao, T.; Huang, J.; Sun, S.; Guo, H.; Wang, J. Green Chem. 2013, 15, 2384. (22) Ramachary, D. B.; Shashank, A. B. Chem. - Eur. J. 2013, 19, 13175. (23) Li, W.; Jia, Q.; Du, Z.; Wang, J. Chem. Commun. 2013, 49, 10187. (24) Seus, N.; Goldani, B.; Lenardão, E. J.; Savegnago, L.; Paixão, M. W.; Alves, D. Eur. J. Org. Chem. 2014, 2014, 1059. (25) Li, W.; Du, Z.; Huang, J.; Jia, Q.; Zhang, K.; Wang, J. Green Chem. 2014, 16, 3003. (26) Saraiva, M. T.; Costa, G. P.; Seus, N.; Schumacher, R. F.; Perin, G.; Paixão, M. W.; Luque, R.; Alves, D. Org. Lett. 2015, 17, 6206. (27) Savegnago, L.; Sacramento, M.; Brod, L. M. P.; Fronza, M. G.; Seus, N.; Lenardão, E. J.; Paixão, M. W.; Alves, D. RSC Adv. 2016, 6, 8021.

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Paulo F. B. Gonçalves: 0000-0002-5348-9028 Diego Alves: 0000-0002-1074-0294 Diogo S. Lüdtke: 0000-0002-9135-4298 1356


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