Water-Compatible Synthesis of 1,2,3-Triazoles under Ultrasonic Conditions by a Cu(I) Complex-Mediated Click Reaction

Abstract

A new monophosphine Cu(I) complex bearing bis(pyrazolyl)methane (L₁) (CuIL₁PPh₃) was synthesized and used as a catalyst for the three-component click reaction from an alkyl halide, sodium azide, and terminal alkyne to furnish 1,4-disubstituted 1,2,3-triazoles in up to 93% yield. The catalyst is highly stable, compatible with oxygen/water, and works with total efficiency under ultrasonic condition. The structure of the complex was studied and confirmed by X-ray crystallography, finding a riveting relationship with its catalytic activity. This sustainable triazoles synthesis is distinguished by its high atom economy, low catalyst loading (up to 0.5 mol %), broad substrate scope, short reaction times, operational simplicity, and an easy gram-scale supply of a functionalized product for subsequent synthetic applications.

Introduction

Sustainable laboratory methods have become the main route for synthetic chemists to carry out research, which had led scientists to improve the scope of their discoveries and reduce pollution during chemical production.¹⁻⁵ Efficient reactions, catalyst use, and water-compatible and/or alternative activation technologies are crucial to minimize cost, energy, environmental impact, and waste. Ultrasound or microwave irradiation (USI or MWI) and mechanochemical mixing are powerful tools in the current sustainable organic synthesis and have been successfully used to expand traditional methods, and thus a plethora of applications have been reported.^2,3 Specifically, ultrasonic synthesis has emerged as one of the most appreciated techniques due to its advantages with respect to conventional thermal methods, such as reaction rate, yield, operational simplicity, purity of the products, and so on.³⁻⁵

Regarding efficient reactions and catalyst use, laboratories of Sharpless (in situ Cu(I) formation from CuSO₄/sodium ascorbate)⁶ and Meldal (CuI/DIPEA)⁷ independently reported that Cu(I) can catalyze the Huisgen cycloaddition to afford 1,4-disubstituted 1,2,3-triazoles under very mild conditions. This reaction satisfies all of the requirements of the term “click chemistry” and is known as copper-catalyzed azide–alkyne cycloaddition (CuAAC).⁸ This reaction has been effectively applied in diverse divisions of science such as organic chemistry,^9,10 drug discovery,^11,12 polymers,¹³ and material sciences¹⁴ because of its ideal atom economy, bio-orthogonality, regiospecificity, high yield, and compatibility with diverse functional groups. Moreover, they are important reports of the click reaction carried out in easily removable or benign solvents such as water.¹⁵

The catalytic system most commonly used for CuAAC employs in situ formation of Cu(I) by the reduction of Cu(II) salts with sodium ascorbate (NaAsc) in water.⁶ Afterward, direct utilization of Cu(I) salts in the presence of Cu(I)-stabilizing N-heterocyclic ligands such as 2,6-bis(2-oxazolinyl)pyridine I(16) and tris(triazolyl)amine-bearing ligands II(17,18) has been widely applied to protect Cu(I) from oxidation and disproportionation (Figure 1). Alternatively, the use of preformed Cu(I) complexes bearing tris(triazol-4-yl)methane-based ligands III(19) has offered unprecedented practicability to catalyze the CuAAC reaction because the tertiary nitrogen (N) atom center of the catalyst behaves both as a donor to Cu(I) and as a proton acceptor. Thus, there is no requirement of a base and deoxygenated conditions (Figure 1).

Figure 1.

Effective N-heterocyclic ligands and Cu(I) complexes for CuAAC reaction.

In the last decade, phosphorus-based Cu(I) complexes including CuBr(PPh₃)₃,²⁰ CuI[P(OEt)₃] and Cu(NO₃)(PPh₃)₂,²¹ and CuBr[PPh₂(OPh-2-OMe)]²² have been used to prepare various 1,2,3-triazoles under very mild reaction conditions. Albeit the use of preformed complexes bearing N-donor ligands or phosphine derivatives has undeniably increased the CuAAC reaction impact, both synthesis and application efficiency of novel catalysts are still desirable.¹⁵⁻²³ Indeed, we have recently reported the synthesis of a Cu(I) coordination polymer [Cu₂(μ-I)₂(μ-L)₂]_n by a self-assembly process between CuI and 1,3-bis(benzotriazol-1-ylmethyl)benzene, as well as its application in the three-component reaction between benzyl bromides 1, sodium azide (2), and terminal alkynes in acetonitrile to furnish 1,2,3-triazoles 4 (Scheme 1a).²³ Despite the ubiquity of the CuAAC reaction, there are a few cases of three-component variants involving in situ generation of organic azides by alternative techniques such as ultrasound, microwave, and continuous flow conditions in aqueous media.²⁴ For example, Sreedhar,²⁵ Mady,²⁶ and Rezki²⁷ reported 1,2,3-triazoles synthesis in reduced reaction times (6–60 min) using ultrasonic baths but in the presence of additives and a high catalyst loading (Scheme 1b). Though there are reports on the application of ultrasonic baths as energy sources to promote chemical reactions, use of a probe-based ultrasonic system allowing excellent parameter control is valuable. Moreover, the probe favors an efficient sonication process because of its highly localized intensity, which means it would be easy to reproduce or scale a given process.²⁸

Scheme 1. Three-Component Synthesis of 1,2,3-Triazole Derivatives 4 under (a) Heating in MeCN, (b) Ultrasound Irradiation, and (c) Our Synthetic Proposal.

Thus far, there has only been one published example of the multicomponent click reaction using ultrasonic homogenizer (Scheme 1b).²⁸ Albeit such sonochemical methods are generally reliable in aqueous medium, most of them employ ultrasonic baths,²⁵⁻²⁷ organic co-solvents,²⁶⁻²⁸ one or more reagents in excess of the stoichiometric amount, and require much larger quantities of CuSO₄, NaAsc, and CuI because the absence of Cu(I)-stabilizing ligands increases the metal center oxidation. To overcome these drawbacks, and due to our interest in sustainable laboratory methods to obtain diverse N-heterocyclic compounds,²⁹⁻³¹ we report here the preparation of a novel Cu(I) complex bearing triphenylphosphine (PPh₃) and bis(3,5-dimethyl-1H-pyrazol-1-yl)methane ligands and their application in the multicomponent click reaction in aqueous media employing an ultrasonic homogenizer (Scheme 1c).

Results and Discussion

To achieve a detailed methodological study, we prepare a new Cu(I) complex bearing bis(3,5-dimethyl-1H-pyrazol-1-yl)methane (L₁) and PPh₃ ligands (CuIL₁PPh₃). Initially, the ligand L₁ was synthesized under known conditions in 68% yield (i.e., 3,5-dimethylpyrazole, KOH, K₂CO₃, and Bu₄NBr in DCM).³² The Cu(I) halide complexes having tertiary phosphine ligands with 1:1, 1:2, 1:3, and 2:3 Cu/PR₃ ratios have been synthesized, and their structures are determined by X-ray crystallography (XRC).³³ The stoichiometry ratio determines the nuclearity of the complexes, while the polymorph outcome can be influenced by the solvent or the procedure used.³⁴ Complexes with a 1:1 Cu/Ligand [CuX(PR₃)] ratio only have been obtained in a tetrameric structure form, as polymorphs are cubane-like or step-like.³⁴ Following the previously reported method,³⁵ we synthesized the complex [CuI(PPh₃)]₄ (A) in 76% yield employing a 1:1 molar ratio stoichiometry of CuI and PPh₃ in acetonitrile (MeCN) at room temperature for 1 h (Scheme 2a). XRC analysis confirmed that this Cu(I) cluster was obtained as a step-like polymorph in a tetrameric structure form (Scheme 2a; see the Supporting Information (SI) for structural details).

Scheme 2. Synthesis of Complexes (a) [CuI(PPh₃)]₄ and (b) CuIL₁PPh₃, and Their X-ray Structures.

The new complex CuIL₁PPh₃ (B) having the ligand L₁ was synthesized in 54% yield after its recrystallization from MeCN at room temperature. Albeit mass spectrometry studies were carried out to establish the new complex stoichiometry, the result was inconclusive. Fortunately, we obtained single crystals suitable for XRC analysis of the complex that confirmed a 1:1 Cu/L1 ratio regardless of the stoichiometry of the reaction. These results are consistent with those found with Cu(I) complexes having neutral bidentate N-donor ligands.³⁶ This complex is stable in air for extended periods of time in the solid state and for several days in solution (Scheme 2b; see the SI for structural details).

The ¹H and ¹³C NMR spectra of CuIL₁PPh₃ were measured in DMSO-d₆, and the appropriate signals of hydrogen and carbon atoms of the ligands L₁ and PPh₃ were observed (see Figures S5 and S6 in the SI). The clear downfield shifts of the methylene group and pyrazolyl ring protons may be explained by increased σ-bonding contribution from the N-donor L₁ to the Cu(I) center. Moreover, the multiplet at 7.38–7.49 ppm integrating for 15 hydrogens confirmed that the complexes have a PPh₃ group. The ¹³C NMR spectrum showed that carbons of the two pyrazolyl rings are equivalent, which support the tetrahedral geometry of complex. Notably, the shift to higher field of ipso-carbons (δ = 133.2 ppm) of the PPh₃ in complex with respect to free PPh₃ (δ = 136.6 ppm) could be explained by increased π-backbonding influence from the metal to PPh₃ ligand, which is consistent with the shorter Cu–P bond length of 2.21 Å (Table S2 in the SI).³⁷

The two synthesized Cu(I) complexes were subsequently studied with respect to their catalytic properties in the three-component click reaction to furnish 1,2,3-triazoles. First, we studied the synthesis of noncommercially available terminal alkynes employing a previously reported method in our laboratory.³⁸ In this way, we established an efficient Cs₂CO₃-promoted method for the O-alkylation of hydroxyaromatic compounds 5a–c and the N-alkylation of benzylamine (5d) with propargyl bromide (6) in anhydrous N,N-dimethylformamide (DMF) at 25 °C for 12 h for obtaining functionalized terminal alkynes 3e–h in good yields (Scheme 3). In all examples, the purity was >95% by ¹H NMR analysis of the crude reaction mixtures.

Scheme 3. Cs₂CO₃-Promoted Chemoselective Alkylation of 5a–d^,

Reaction conditions: equimolar amounts (6.77 mmol) of 5a–d, propargyl bromide 6, and Cs₂CO₃ in 5.0 mL of DMF at 25 °C for 12 h.

2.0 equiv of 5d was used.

Afterward, benzyl bromide (1a), sodium azide (2), and phenylacetylene (3a) were chosen as model substrates aiming to explore the Cu(I) complexes obtained in the synthesis of 1-benzyl-4-phenyl-1H-1,2,3-triazole (4a). All experiments were performed using normal atmospheric conditions and stoichiometric amounts of the reagents (Table 1). First, we tested the reaction with a range of temperatures, solvents, Cu(I) catalysts, and by examining the effect of USI compared to conventional heating to define the best reaction conditions. Both [CuI(PPh₃)]₄ and CuIL₁PPh₃ complexes were tested in various experiments at the same time to find the best catalytic system. In all cases, the expected product 4a was observed exclusively, by ¹H NMR analysis of the crude reaction mixtures, without any trace of its 1,5-regioisomer, and yield was determined using dibromomethane as an internal standard. As expected, the absence of the Cu(I) catalyst did not lead to product (Table 1, entry 1). Concerning the solvent, it is clear that highly polar solvents afforded higher yields using a preheated sand bath at 40 °C for 6 h (Table 1, entries 2–5). Albeit water was found to be the best solvent, the reaction can be performed in polar aprotic solvents such as tetrahydrofuran (THF) and acetonitrile (MeCN) without losing efficacy. The absence of solvent resulted in an acceptable conversion, but heating the reaction at 60 °C in water increases the conversion of 4a (Table 1, entries 6 and 7). The reaction proceeds equally well at 6 and 12 h, which suggests that a long reaction time is not a critical factor; conversely, when the reaction was conducted at lower reaction times and higher temperatures, the conversion of 4a gets diminished (Table 1, entries 7–10).

Table 1. Optimization of the Best Solvent, Catalyst, and Temperature for Triazole 4a Synthesis^a.

entry	solvent	catalyst	T (°C)	conv (%)b
1	H2O		40	NDc
2	THF	CuIL1PPh3 (A)	40	71 (66)
3	MeCN	CuIL1PPh3 (A)	40	78 (73)
4	EtOH	CuIL1PPh3 (A)	40	80 (74)
5	H2O	CuIL1PPh3 (A)	40	88 (81)
6		CuIL1PPh3 (A)	40	56 (51)
7	H2O	CuIL1PPh3 (A)	60	>98 (92)
8d	H2O	CuIL1PPh3 (A)	60	>98 (>98)
9e	H2O	CuIL1PPh3 (A)	60	40 (35)
10	H2O	CuIL1PPh3 (A)	90	92 (87)
11f	H2O	CuIL1PPh3 (A)	60	97 (90)
12f	H2O	CuIL1PPh3 (A)	30	70 (64)
13f	H2O	CuCl	60	30
14f	H2O	CuBr	60	37
15f	H2O	CuI	60	51
16f	H2O	CuOAc	60	54
17f	H2O	CuSO4/NaAsc	60	42

^aAll experiments were performed with equimolar amounts (0.50 mmol) of 1a, 2, and 3a, and 5 mol % catalyst in 2.0 mL of solvent under stirring for 6 h by conventional heating.

^bConversions were determined by ¹H NMR of the crude reaction mixtures using CH₂Br₂ as an internal standard, and those shown in parentheses were obtained with [CuI(PPh₃)]₄ (A).

^cTriazole was undetectable by ¹H NMR of the crude reaction mixture.

^dReaction time 12 h.

^eReaction time 1 h.

^fReaction under US irradiation (20 kHz, 300 W) at 60 °C for 30 min.

In a modified protocol, we carried out the reaction under USI to furnish a slightly lower yield in a shorter reaction time than under conventional heating based on thermal conduction and convection (Table 1, entry 11 vs 7). The shorter reaction time could be due to ultrasonic cavitation by the probe immersed in the reaction mixture, which enhances mass transfer rates and catalyst efficacy. In this process, an inverse temperature effect on cavitation intensity takes place due to generation of vaporos cavities, reduced bubble collapse, and thus high boiling solvents are ideal for reactions that require high temperatures.^3−5,28,30 Consequently, the effect of temperature was evaluated keeping the same reaction time, but the conversion of 4a significantly diminished at lower temperatures (Table 1, entry 11 vs 12). In all cases, [CuI(PPh₃)]₄ showed a catalytic activity somewhat lower than that of CuIL₁PPh₃ (Table 1, entries 2–12), though the conversion largely decreased in the presence of Cu(I) salts without any additive, as well as with the most commonly used catalytic system CuSO₄/NaAsc (Table 1, entries 13–17). Pleasantly, the US-assisted reaction in water resulted in the total starting materials conversion into 4a in the presence of 5 mol % CuIL₁PPh₃ (Table 1, entry 11).

Aiming to improve the process, we screened the catalyst loading, reaction time, and ultrasound power in the absence of any nitrogen-based ligand/additive (Table 2). The reactions by USI were performed using an ultrasonic reactor (Vibra-Cell VCX 750 probe) in pulse mode at 20 kHz and 40% wave amplitude. When CuIL₁PPh₃ loading was decreased down to 1 mol %, excellent conversions were still obtained keeping the reaction time and ultrasound power (Table 2, entries 1–4), and only a moderate conversion into 4a was obtained with 0.5 mol % catalyst (Table 2, entry 5). Moreover, decreasing the reaction time and US power while maintaining the catalyst loading led to moderate conversions (Table 2, entries 6–9). These results suggest that the best reaction conditions are achieved when it is sonicated in the presence of 1 mol % catalyst for 30 min in aqueous medium (Table 2, entry 4). From these optimized reaction conditions, we tested the ligand effects by using them in combination with the Cu(I) catalyst (Table 3). The addition of 10 mol % free ligands (PPh₃ and/or L₁) to the reaction mixtures having CuIL₁PPh₃ (1 mol %) had little effect in conversions (Table 3, entries 1–3). Importantly, using 1 mol % Cu(I) catalyst, the new preformed complex CuIL₁PPh₃ achieved the best catalytic result with respect to its precursor [CuI(PPh₃)]₄ and the possible in situ generation of CuIL₁PPh₃ (Table 2, entry 4 vsTable 3, entries 4–6).^39,40 We think this might be due to the low solubility of L₁ in aqueous medium, which would be deleterious for the interaction with the tetrameric complex [CuI(PPh₃)]₄.

Table 2. Optimization of Catalytic Load and US Power for Triazole 4a Synthesis^a.

entry	power (W)	[Cu] (mol %)	t (min)	conv (%)b
1	300	4	30	>96
2	300	3	30	>96
3	300	2	30	>96
4	300	1	30	95
5	300	0.5	30	63
6	300	1	20	70
7	300	1	10	41
8	200	1	30	64
9	100	1	30	39

^aExperiments were performed with equimolar amounts (0.50 mmol) of 1a, 2, and 3a, and 0.5–4 mol % catalyst in 2.0 mL of distilled water under USI (20 kHz, 100–300 W) at 60 °C for 10–30 min.

^bConversions were determined by ¹H NMR using CH₂Br₂ as an internal standard.

Table 3. Ligand Effects for the One-Pot US-Assisted Model Reaction^a.

entry	PPh3 (mol %)c	L1 (mol %)c	conv (%)b
1a	10	10	96
2a	10		95
3a		10	95
4d			71
5d		10	83
6d		30	86

^aReaction conditions: equimolar amounts (0.50 mmol) of 1a, 2, and 3a, and 1 mol % CuIL₁PPh in 2.0 mL of distilled water under US irradiation (20 kHz, 300 W/60 °C, 30 min).

^bConversions were determined by ¹H NMR using CH₂Br₂ as an internal standard.

^cPPh₃ and/or L₁ were used as additive ligands.

^dReaction with [CuI(PPh₃)]₄ (1 mol %) and L₁ (10–30 mol %) by possible in situ generation of CuIL₁PPh₃.

With an optimized catalytic system in hand (Table 2, entry 4), we next investigated the potential scope of reactants for this one-pot ultrasonic approach by CuAAC reactions under very mild conditions (Scheme 4). In all cases, the 1,4-disubstituted 1,2,3-triazoles 4a–l were obtained in high conversions (up to 99%) and good yields (up to 93%) after a simple purification process, showing a broad scope and high tolerance of functional groups in aqueous media. As expected, benzyl bromide (1a) and p-chlorobenzyl iodide (1c) reacted very well, providing triazoles 4a and 4c in 90–93% yields, whereas the same triazole 4a was obtained in 75% yield with the unreactive benzyl chloride (1b). No loss of efficacy was observed for p-fluorophenylacetylene, leading to the product 4b in a good yield. The next step to show reaction generality was exploring the terminal alkynes hydroxyarene derivatives 3e–g to give the expected triazoles 4d–f in 88–93% yields. From these aryloxy-triazoles, both naphthyl- and coumarin-substituted 4e–f could be promising fluorophores in photophysical applications; indeed, coumarin derivatives have been applied as fluorescent probes to metal-ion sensing and visualize the metabolism of cysteine in cells^41,42 (Scheme 4).

Scheme 4. US-Assisted Synthesis of Triazoles 4a–l by CuAAC Reactions^,,,,,,

Reaction conditions: equimolar amounts (0.50 mmol) of 1a–e, 2, and 3a–h, and catalyst (1 mol %) in 2.0 mL of water under USI (20 kHz, 300 W) at 60 °C for 30 min.

Reaction run with benzyl bromide (1a).

Reaction run with benzyl chloride (1b).

Reaction run with 4-chlorobenzyl iodide.

Reaction run with 1.0 mmol of 1a.

Reaction run with 1,3-bis(bromomethyl)-5-methylbenzene (1d), 2 (1.0 mmol), and phenylacetylene (3a, 1.0 mmol).

Reaction run with 2,6-bis(chloromethyl)pyridine (1c), 2 (1.0 mmol), and 3a (1.0 mmol).

On the other hand, different functional groups were very well tolerated, such as branched alcohol and silyl ethers, which allowed us to obtain the 1,2,3-triazoles 4g–h that could be used as platforms to obtain more important and complex structures. In addition, the pseudo-four-component reaction of excess benzyl bromide (1a) with sodium azide (2) and N-benzylprop-2-yn-1-amine (3h) furnished the triazole 4i bearing three benzyl units, probably by an S_N2/CuAAC/N-alkylation sequence, allowing the formation of four covalent bonds. In a more challenging version of this approach, 1,3-bis(bromomethyl)-5-methyl-benzene (1d) and 2,6-bis(chloromethyl)pyridine (1e) provided the bis-triazoles 4j–l in good yields by a pseudo-five-component process with the formation of six covalent bonds. Curiously, the 2,6-bis(triazolyl)pyridine 4l could be used as an N-heterocyclic ligand for the preparation of coordination complexes and/or for metal-ion sensing (Scheme 4).⁴²⁻⁴⁴

The ultrasound-assisted multicomponent synthesis developed in this work was distinguished by its regiospecificity, low catalyst loading (1 mol %), compatibility with oxygen/water, broad substrate scope, operational simplicity, reduced reaction times, high atom economy, and environmental friendliness. Pleasingly, this protocol fulfills at least 8 out of the 12 principles of green chemistry, including (1) prevention, (2) atom economy, (3) less hazardous chemical syntheses, (4) safer solvents and auxiliaries, (5) energy-efficient design, (6) reduced derivatives, (7) catalysis, and (8) inherently safer chemistry for accident prevention.⁴⁵ It should be noted that although the yields of the 1,2,3-triazoles obtained in this work are comparable to those already reported in the literature,⁴⁶⁻⁵² the new Cu(I) complex under ultrasonic conditions dramatically decrease reaction time from hours to minutes. Moreover, this approach provides products in pure form by the formation of three bonds in one step and without the need of large quantities of copper source and any kind of additive or organic co-solvent,⁵³ rendering our developed methodology an ideal multicomponent click reaction.

At this stage of our investigation, we decided to run the click reaction under ultrasound on a 7 g scale to obtain a key product for potential later synthetic applications. Scalability was tested in the benzyl bromide (1b, 25 mmol scale) reaction with the terminal alkyne 3e and sodium azide (2) to afford the product 4d. Analytically pure 1,2,3-triazole 4d (6.982 g) was obtained without requiring column chromatography purification. Moreover, the overall catalyst loading was decreased from 1.0 (Scheme 4) to 0.50 mol % (Scheme 5). Increasing the scale also resulted in a slight increase in the yield of 4d from 88 to 90%. Importantly, N-benzyl-1,2,3-triazole 4d containing a nitro group can be converted into an amine functional group. Therefore, the biological effect of such post-functionalized 1,2,3-triazole-based compound, as well as other possible applications, would be enhanced.

Scheme 5. Multigram-Scale Synthesis of N-benzyl-1,2,3-triazole 4d.

As part of this study, since the catalytic activity of the two obtained complexes was studied and their structures were solved by XRC, we carried out a full structural analysis aiming to find a relationship between these results. Complexes [CuIPPh₃]₄ and CuIL₁PPh₃ crystallize in the monoclinic I2/c and triclinic P-1 space groups as tetra- and mononuclear molecules, respectively. Cu(I) describes tetrahedral coordination geometries in both complexes, though an unusual trigonal planar geometry is observed in [CuIPPh₃]₄, allowing a metal–metal bonding interaction between Cu atoms. Despite the differences in the molecular structures, bond distances of Cu–P (≈2.2 Å) and Cu–I (≈2.5–2.7 Å) are similar. In the supramolecular structure, no classic hydrogen bonds were found causing that only van der Waals forces are involved in the three-dimensional structure. Crystallographic data and a deeper description of the crystal structures are provided in the SI. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of FMO (frontier molecular orbital) energy levels for complexes were computed from the crystallographic results (Scheme 6), and thus we managed to find a notable correlation with their catalytic properties (see the SI for details).

Scheme 6. Computed Energy Levels HOMO–LUMO for (a) [CuIPPh₃]₄ and (b) CuIL₁PPh₃.

Results using the crystallographic information files (.cif) by STO-3G basis set at the Hartree–Fock level theory.

The calculations were carried out by the STO-3G basis set at the Hartree–Fock level of theory executed in CrystalExplorer⁵⁴ using the crystallographic information files (.cif) obtained from the X-ray diffraction measurements. These FMO results show that the new complex has stronger hardness than [CuIPPh₃]₄, with HOMO–LUMO energy gap values of 7.14 and 2.56 eV, respectively. Likewise, both FMOs of CuIL₁PPh₃ exhibit a greater metal character than those of the tetrameric complex; indeed, the LUMO of mononuclear complex has a very strong metal character mostly located around the copper atom, and thus, this complex is more electrophilic. Consequently, the interaction between reagents and the catalyst in the Cu(I)-mediated click reaction to form the 1,2,3-triazoles 4a–l could be more favored with the new complex (see Table 3 and Scheme 6). Probably, these findings clarify the high catalytic activity of CuIL₁PPh₃ in the US-assisted click reaction studied by us, which is predominantly governed by both electrostatic interactions and steric effects (see the SI for more details).⁵⁵⁻⁵⁷

Conclusions

In summary, we have synthesized a new Cu(I) complex bearing bis(3,5-dimethyl-1H-pyrazol-1-yl)methane and PPh₃ ligands that served as an effective catalyst to obtain 1,4-disubstituted 1,2,3-triazoles in yields up to 93%. This complex type is scarce, but was prepared using readily available reagents, and could be successfully handled in air and water without any particular precautions. Gratifyingly, the structure of CuIL1PPh₃ complex was confirmed by XRC analysis; in addition, we managed to find a key connection with its high catalytic activity using the CE-HF model. As far as we know, this is the first report of using an ultrasonic homogenizer combined with a coordination complex in the synthesis of triazoles via a three-component click reaction from an alkyl halide, sodium azide, and terminal alkyne in the absence of any base or additive. Some more complex reactions are also possible for the controlled assembly of up to five components and the formation of up to six covalent bonds in a cascade process.

This synthetic methodology is simple and efficient to prepare functionalized triazoles, and the results found are evidence that the economical and easily accessible CuIL₁PPh₃ complex could assist the possibility for the widespread demand. Likewise, its application allows significant advantages including high atom economy, low catalyst loading, environmental friendliness, broad substrate scope under exceedingly mild reaction condition, high yield, shorter reaction time, operational simplicity, reduced alkyne–alkyne homocoupling products, and handling of volatile alkynes and unstable organic azides in air and water. In addition, triazoles bearing pyridine, naphthalene, and coumarin could be used in the design of fluorescent probes for species sensing of biomedical and environmental interest, among other applications. Ultimately, an effective scalable sequence to obtain a nitro-substituted triazole has been developed.

Experimental Section

General Information

All reagents were purchased from commercial sources and used without further purification. All starting materials were weighed and handled in air at room temperature. Progression of reactions and purifications of products were monitored by thin-layer chromatography (TLC) on silica gel (60 F₂₅₄) using UV light as a visualization agent. Silica gel (230–400 mesh) was used for flash chromatography. Ultrasound-assisted reactions were performed using an ultrasonic Sonics Vibra-Cell VCX 750 probe equipped with both a tapered micro-tip of 1/4″ and a thermocouple. Reactions under ultrasound were performed using a 25 mL glass two-neck pear-shaped flask (TNPSF). NMR spectra were recorded at 400 MHz (¹H) and 101 MHz (¹³C{¹H}) at 298 K using tetramethylsilane (0 ppm) as the internal reference. DEPT spectra were used for the assignment of carbon signals. Chemical shifts (δ) are given in ppm, and coupling constants (J) are given in hertz. The following abbreviations are used for multiplicities: s = singlet, d = doublet, t = triplet, and m = multiplet. Melting points were collected using a capillary melting point apparatus and are uncorrected. High-resolution mass spectroscopy (HRMS) data were recorded using a Q-TOF spectrometer via electrospray ionization (ESI, 4000 V). The FTIR spectrum of the CuIL₁PPh₃ complex was recorded on a spectrometer using KBr pellets (400–4000 cm^–1), while the Raman spectrum was performed on a Raman microscope (200–2400 cm^–1). Elemental analysis (C, H, and N) of the complex was performed with a CHNS/O Analyzer. Crystallographic data were recorded at 25 °C on a diffractometer using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). Structures were solved using an interactive algorithm,⁵⁸ later completed by a difference Fourier map, and refined using the program SHELXL2014,⁵⁹ and the graphic material was prepared using the Mercury 3.10 software. The ligand bis(3,5-dimethyl-1H-pyrazol-1-yl)methane (L₁)³² and the precursor complex [CuIPPh₃]₄³⁵ were synthesized as described in the literature. Crystals suitable for X-ray structure analysis of [CuIPPh₃]₄ were obtained from acetonitrile by slow evaporation of the solution at room temperature. The noncommercially available alkynes 3e–h were prepared by a method developed in our laboratory.³⁸

Synthesis and Characterization

Synthesis of CuIL₁PPh₃ Complex

A mixture of 2 equiv of bis(3,5-dimethyl-1H-pyrazol-1-yl)methane (L₁, 114 mg, 0.56 mmol) in dichloromethane (5.0 mL) was added to a suspension with 1.0 equiv of Cu(I) (129 mg, 0.28 mmol) from precursor [CuIPPh₃]₄ in the same solvent (7.0 mL). The resulting mixture was stirred at 40 °C for 2 h, after which the reaction mixture was cooled to room temperature. Subsequently, the suspension was filtered, the filtrate was dried under reduced pressure, and the solid residue was recrystallized from acetonitrile to afford the pure CuIL₁PPh₃ complex as a white solid (98.1 mg, 54%); mp 192–194 °C (amorphous). Crystals suitable for X-ray structure analysis for complex CuIL₁PPh₃ were obtained from acetonitrile by slow evaporation of the solution at room temperature (see the SI for datails). FTIR (KBr): 420, 497, 694, 740, 810, 1096, 1284, 1431, 1558, 2916, 3051 cm^–1; Raman: 209, 450, 487, 1000, 1096, 1465, 1587, 2923, 3010, 3054 cm^–1; ¹H NMR (400 MHz, DMSO-d₆): δ = 1.96 (s, 6H, CH₃), 2.38 (s, 6H, CH₃), 5.92 (s, 2H, CH₂), 6.22 (s, 2H, CH), 7.38–7.49 (m, 15H, PPh₃) ppm; ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ = 10.5 (CH₃), 13.7 (CH₃), 57.0 (CH₂), 106.1 (CH), 128.6/128.8 (d, J = 9.5 Hz, CHm), 130.0 (Cp), 133.1/133.4 (d, J = 28.6 Hz, Ci), 133.5/133.6 (d, J = 15.4 Hz, CHo), 140.6 (C), 149.1 (C) ppm. Anal. calcd for C₂₉H₃₁N₄IPCu: C 53.01; H 4.76; N 8.53%. Found: C 53.01; H 4.68; N 8.26%.

General Procedure for the Synthesis of Terminal Alkynes 3e–h

An equimolar mixture (6.77 mmol) of cesium carbonate (Cs₂CO₃, 2.2 g) and the respective nucleophile 5a–d in anhydrous DMF (5.0 mL) was stirred at room temperature for 30 min. To this white suspension was added the propargyl bromide solution 80 wt % in toluene (6, 754 μL) in one portion, and the resulting reaction mixture was stirred at room temperature for 12 h. Then, the reaction mixture was filtered and rinsed with ethyl acetate (3 × 10.0 mL). The combined organic layers were washed with brine (3 × 10.0 mL), dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluent: CH₂Cl₂) to afford the pure terminal alkyne 3e–h, which were identified by comparison of its spectroscopic data with those reported in the literature.

1-Nitro-4-(prop-2-yn-1-yloxy)benzene (3e)

Following the general procedure, the reaction of 4-nitrophenol (5a, 942 mg, 6.77 mmol), propargyl bromide in toluene (6, 754 μL, 6.77 mmol), and Cs₂CO₃ (2206 mg, 6.77 mmol) in 5.0 mL of anhydrous DMF at 25 °C for 12 h afforded compound 3e as a yellow solid (1055 mg, 88%); mp 119–120 °C (ref⁶⁰, 118–119 °C). ¹H NMR (400 MHz, CDCl₃): δ = 2.59 (t, J = 2.4 Hz, 1H), 4.80 (d, J = 2.4 Hz, 2H), 7.06 (d, J = 9.2 Hz, 2H), 8.23 (d, J = 9.2 Hz, 2H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 56.3 (CH₂), 76.8 (CH), 77.12 (C), 115.0 (CH), 125.9 (CH), 142.1 (C), 162.3 (C) ppm. HRMS (ESI+): calcd for C₉H₈NO₃⁺ 178.0499 [M + H]⁺; found 178.0498. These NMR data matched previously reported data.⁶⁰

2-(Prop-2-yn-1-yloxy)naphthalene (3f)

Following the general procedure, the reaction of 2-naphthol (5b, 976 mg, 6.77 mmol), propargyl bromide in toluene (6, 754 μL, 6.77 mmol), and Cs₂CO₃ (2206 mg, 6.77 mmol) in 5.0 mL of anhydrous DMF at 25 °C for 12 h afforded compound 3f as a brown solid (1036 mg, 84%); mp 60–62 °C (ref⁶¹, 48–50 °C). ¹H NMR (400 MHz, CDCl₃): δ = 2.55 (t, J = 2.4 Hz, 1H), 4.79 (d, J = 2.4 Hz, 2H), 7.18 (dd, J = 3.0, 8.2 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.5, 1H), 7.74–7.78 (m, 3H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 55.8 (CH₂), 75.7 (CH), 78.5 (C), 107.4 (CH), 118.7 (CH), 124.0 (CH), 126.5 (CH), 126.9 (CH), 127.7 (CH), 129.3 (C), 129.6 (CH), 134.3 (C), 155.4 (C) ppm. HRMS (ESI+): calcd for C₁₃H₁₁O⁺ 183.0804 [M + H]⁺; found 183.0806. These NMR data matched previously reported data.⁶¹

7-(Prop-2-yn-1-yloxy)-2H-chromen-2-one (3g)

Following the general procedure, the reaction of 7-hydroxycoumarin (5c, 1098 mg, 6.77 mmol), propargyl bromide in toluene (6, 754 μL, 6.77 mmol), and Cs₂CO₃ (2206 mg, 6.77 mmol) in 5.0 mL of anhydrous DMF at 25 °C for 12 h afforded compound 3g as a white solid (989 mg, 73%); mp 125–126 °C (ref⁶², 118 °C). ¹H NMR (400 MHz, CDCl₃): δ = 2.58 (t, J = 2.4 Hz, 1H), 4.76 (d, J = 2.4 Hz, 2H), 6.28 (d, J = 9.2 Hz, 1H), 6.90–6.94 (m, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 9.6 Hz, 1H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 56.2 (CH₂), 76.6 (CH), 77.4 (C), 102.1 (CH), 113.1 (CH), 113.2 (C), 113.6 (CH), 128.8 (CH), 143.3 (CH), 155.6 (C), 160.5 (C), 161.0 (C) ppm. HRMS (ESI+): calcd for C₁₂H₉O₃⁺ 201.0546 [M + H]⁺; found 201.0549. These NMR data matched previously reported data.⁶²

N-Benzylprop-2-yn-1-amine (3h)

Following the general procedure, the reaction of benzylamine (5d, 1474 μL, 13.50 mmol), propargyl bromide in toluene (6, 754 μL, 6.77 mmol), and Cs₂CO₃ (2206 mg, 6.77 mmol) in 5.0 mL of anhydrous DMF at 25 °C for 12 h afforded compound 3h as a colorless oil (698 mg, 71%). ¹H NMR (400 MHz, CDCl₃): δ = 2.26 (t, J = 2.4 Hz, 1H), 3.42 (d, J = 2.4 Hz, 2H), 3.88 (s, 2H), 7.23–7.36 (m, 5H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 37.3 (CH₂), 52.3 (CH₂), 71.6 (CH), 82.0 (C), 127.2 (CH), 128.4 (CH), 128.5 (CH), 139.4 (C) ppm. HRMS (ESI+): calcd for C₁₀H₁₂N⁺ 146.0964 [M + H]⁺; found 146.0959. These NMR data matched previously reported data.³⁸

General Procedure for the Synthesis of 1,2,3-Triazoles 1,4-Disubstituted 4a–l

A mixture of the alkyl halide 1 (0.50 mmol), sodium azide (2, NaN₃, 0.50 mmol), terminal alkyne 3 (0.50 mmol), and CuIL₁PPh₃ complex (3.3 mg, 1 mol %) in distilled water (2.0 mL) was placed in a 25 mL two-neck flask. The mixture was directly irradiated with an ultrasonic probe (20 kHz and 300 W, 40% wave amplitude) at 60 °C and maintained at this temperature for 30 min. The ultrasound probe was placed in one neck, and the temperature sensor was placed in the other. The resulting precipitate was filtered, washed with H₂O, and then purified by flash chromatography on silica gel (eluent/eluent: CH₂Cl₂/CH₃OH 50:1 to 100:1 v/v) to afford the pure 1,2,3-triazoles 1,4-disubstituted 4a–l.

1-Benzyl-4-phenyl-1H-1,2,3-triazole (4a)

The general procedure at 60 °C for 30 min between benzyl bromide (1a, 59 μL, 0.50 mmol), sodium azide (2, 32 mg, 0.50 mmol), ethynylbenzene (3a, 55 μL, 0.50 mmol), and CuIL₁PPh₃ (3.3 mg, 1 mol %) afforded compound 4a as a white solid (100 mg, 85%); mp 132–133 °C (ref⁴⁶, 130 °C). ¹H NMR (400 MHz, CDCl₃): δ = 5.57 (s, 2H), 7.29–7.33 (m, 3H), 7.35–7.41 (m, 5H), 7.66 (s, 1H), 7.81 (d, J = 7.2 Hz, 2H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 54.2 (CH₂), 119.5 (CH), 125.7 (CH), 128.1 (CH), 128.2 (CH), 128.8 (CH), 129.1 (CH), 130.5 (C), 134.7 (C), 148.2 (C) ppm. HRMS (ESI+): calcd for C₁₅H₁₄N₃⁺ 236.1182 [M + H]⁺; found 236.1188. These NMR data matched previously reported data.⁴⁶

1-Benzyl-4-(4-fluorophenyl)-1H-1,2,3-triazole (4b)

The general procedure at 60 °C for 30 min between benzyl bromide (1a, 59 μL, 0.50 mmol), sodium azide (2, 32 mg, 0.50 mmol), 1-ethynyl-4-fluorobenzene (3c, 60 mg, 0.50 mmol), and CuIL₁PPh₃ (3.3 mg, 1 mol %) afforded compound 4c as a white solid (102 mg, 81%); mp 117 °C (ref⁴⁷, 113–115 °C). ¹H NMR (400 MHz, CDCl₃): δ = 5.56 (s, 2H), 7.07 (t, J = 8.8 Hz, 2H), 7.29–7.40 (m, 5H), 7.61 (s, 1H), 7.76 (m, 2H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 54.3 (CH₂), 115.8 (CH, ²J_C–F = 22.0 Hz), 119.3 (CH), 126.8 (C, ⁴J_C–F = 3.1 Hz), 127.4 (CH, ³J_C–F = 8.1 Hz), 128.1 (CH), 128.8 (CH), 129.2 (CH), 134.6 (C), 147.4/162.7 (C, ¹J_C–F = 248.2 Hz), 161.4 (C) ppm. HRMS (ESI+): calcd for C₁₅H₁₃FN₃⁺ 254.1088 [M + H]⁺; found 254.1092. These NMR data matched previously reported data.⁴⁷

1-(4-Chlorobenzyl)-4-phenyl-1H-1,2,3-triazole (4c)

The general procedure at 60 °C for 30 min between 1-chloro-4-(iodomethyl)benzene (1c, 126 mg, 0.50 mmol), sodium azide (2, 32 mg, 0.50 mmol), ethynylbenzene (3a, 55 μL, 0.50 mmol), and CuIL₁PPh₃ (3.3 mg, 1 mol %) afforded compound 4c as a white solid (111 mg, 82%); mp 135–136 °C (ref,⁴⁸ 132–134 °C). ¹H NMR (400 MHz, CDCl₃): δ = 5.54 (s, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.30–7.42 (m, 5H), 7.67 (s, 1H), 7.79 (d, J = 7.2 Hz, 2H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 53.4 (CH₂), 119.4 (CH), 125.7 (CH), 128.3 (CH), 128.8 (CH), 129.3 (CH), 130.3 (C), 133.2 (C), 134.8 (C), 148.4 (C) ppm. HRMS (ESI+): calcd for C₁₅H₁₃ClN₃⁺ 270.0793 [M + H]⁺; found 270.0797. These NMR data matched previously reported data.⁴⁸

1-Benzyl-4-((4-nitrophenoxy)methyl)-1H-1,2,3-triazole (4d)

The general procedure at 60 °C for 30 min between benzyl bromide (1a, 59 μL, 0.50 mmol), sodium azide (2, 32 mg, 0.50 mmol), 1-nitro-4-(prop-2-yn-1-yloxy)benzene (3e, 88 mg, 0.50 mmol), and CuIL₁PPh₃ (3.3 mg, 1 mol %) afforded compound 4d as a yellow pale solid (136 mg, 88%); mp 103–104 °C (ref⁴⁸, 94–96 °C). ¹H NMR (400 MHz, CDCl₃): δ = 5.27 (s, 2H), 5.55 (s, 2H), 7.05 (d, J = 9.2 Hz, 2H), 7.27–7.30 (m, 2H), 7.38–7.41 (m, 3H), 7.56 (s, 1H), 8.19 (d, J = 9.2 Hz, 2H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 54.4 (CH₂), 62.4 (CH₂), 114.8 (CH), 123.0 (CH), 125.9 (CH), 128.2 (CH), 128.3 (CH), 129.2 (CH), 134.2 (C), 141.9 (C), 143.2 (C), 163.1 (C) ppm. HRMS (ESI+): calcd for C₁₆H₁₅N₄O₃⁺ 311.1139 [M + H]⁺; found 311.1143. These NMR data matched previously reported data.⁴⁸

1-Benzyl-4-((naphthalen-2-yloxy)methyl)-1H-1,2,3-triazole (4e)

The general procedure at 60 °C for 30 min between benzyl bromide 1a (59 μL, 0.50 mmol), sodium azide (2, 32 mg, 0.50 mmol), 2-(prop-2-yn-1-yloxy)naphthalene (3f, 91 mg, 0.50 mmol), and CuIL₁PPh₃ (3.3 mg, 1 mol %) afforded compound 4e as a white solid (143 mg, 91%); mp 157–158 °C (ref⁴⁹, 141–143 °C). ¹H NMR (400 MHz, CDCl₃): δ = 5.29 (s, 2H), 5.52 (s, 2H), 7.15 (m, 1H), 7.23–7.27 (m, 3H), 7.32–7.39 (m, 4H), 7.44 (t, J = 7.4 Hz, 1H), 7.55 (s, 1H), 7.72–7.76 (m, 3H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 54.2 (CH₂), 62.1 (CH₂), 107.2 (CH), 118.9 (CH), 122.7 (CH), 124.0 (CH), 126.5 (CH), 127.0 (CH), 127.7 (CH), 128.2 (CH), 128.9 (CH), 129.2 (CH), 129.2 (C), 129.6 (CH), 134.4 (C), 134.5 (C), 144.6 (C), 156.2 (C) ppm. HRMS (ESI+): calcd for C₂₀H₁₈N₃O⁺ 316.1444 [M + H]⁺; found 316.1445. These NMR data matched previously reported data.⁴⁹

7-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (4f)

The general procedure at 60 °C for 30 min between benzyl bromide 1a (59 μL, 0.50 mmol), sodium azide (2, 32 mg, 0.50 mmol), 7-(prop-2-yn-1-yloxy)-2H-chromen-2-one (3g, 100 mg, 0.50 mmol), and CuIL₁PPh₃ (3.3 mg, 1 mol %) afforded compound 4f as a white solid (155 mg, 93%); mp 155–156 °C (ref⁵⁰, 154–155 °C). ¹H NMR (400 MHz, CDCl₃): δ = 5.23 (s, 2H), 5.55 (s, 2H), 6.26 (d, J = 9.6 Hz, 1H), 6.91 (m, 2H), 7.29 (m, 2H), 7.39 (m, 4H), 7.57 (s, 1H), 7.63 (d, J = 9.6 Hz, 1H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 54.4 (CH₂), 62.3 (CH₂), 102.1 (CH), 112.8 (CH), 113.0 (C), 113.5 (CH), 128.2 (CH), 128.9 (CH), 129.0 (CH), 129.2 (CH), 134.3 (C), 143.3 (CH), 155.7 (C), 161.1 (C), 161.3 (C) ppm. HRMS (ESI+): calcd for C₁₉H₁₆N₃O₃⁺ 334.1186 [M + H]⁺; found 334.1195. These NMR data matched previously reported data.⁵⁰

2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-ol (4g)

The general procedure at 60 °C for 30 min between benzyl bromide 1a (59 μL, 0.50 mmol), sodium azide (2, 32 mg, 0.50 mmol), 2-methyl-3-butyn-2-ol (3c, 48 μL, 0.50 mmol), and CuIL₁PPh₃ (3.3 mg, 1 mol %) afforded compound 4g as a white solid (88 mg, 81%); mp 84–85 °C (ref⁴⁶, 80–81 °C). ¹H NMR (400 MHz, CDCl₃): δ = 1.60 (s, 6H), 2.70 (br s, 1H), 5.49 (s, 2H), 7.26–7.28 (m, 2H), 7.35–7.40 (m, 4H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 30.4 (CH₃), 54.1 (CH₂), 68.5 (C), 119.0 (CH), 128.1 (CH), 128.7 (CH), 129.1 (CH), 134.6 (C), 156.0 (C) ppm. HRMS (ESI+): calcd for C₁₂H₁₆N₃O⁺ 218.1288 [M + H]⁺; found 218.1280. These NMR data matched previously reported data.⁴⁶

1-Benzyl-4-(trimethylsilyl)-1H-1,2,3-triazole (4h)

The general procedure at 60 °C for 30 min between benzyl bromide 1a (59 μL, 0.50 mmol), sodium azide (2, 32 mg, 0.50 mmol), trimethylsilylacetylene (3d, 69 μL, 0.50 mmol), and CuIL₁PPh₃ (3.3 mg, 1 mol %) afforded compound 4h as a white solid (90 mg, 78%); mp 58–59 °C (ref⁴⁶, 71–72 °C). ¹H NMR (400 MHz, CDCl₃): δ = 0.29 (s, 9H), 5.55 (s, 2H), 7.26–7.28 (m, 2H), 7.34–7.38 (m, 3H), 7.42 (s, 1H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = −1.1 (CH₃), 53.4 (CH₂), 128.1 (CH), 128.6 (CH), 128.7 (CH), 129.0 (CH), 135.0 (C), 147.1 (C) ppm. HRMS (ESI+): calcd for C₁₂H₁₈N₃Si⁺ 232.1265 [M + H]⁺; found 232.1271. These NMR data matched previously reported data.⁴⁶

N,N-Dibenzyl-1-(1-benzyl-1H-1,2,3-triazol-4-yl)methanamine (4i)

The general procedure at 60 °C for 30 min between benzyl bromide (1a, 121 μL, 1.02 mmol), sodium azide (2, 32 mg, 0.50 mmol), N-benzylprop-2-yn-1-amine (3h, 73 mg, 0.50 mmol), and CuIL₁PPh₃ (3.3 mg, 1 mol %) afforded compound 4i as a white solid (160 mg, 87%); mp 83–85 °C. ¹H NMR (400 MHz, CDCl₃): δ = 3.59 (s, 4H), 3.74 (s, 2H), 5.52 (s, 2H), 7.20–7.40 (m, 16H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 48.2 (CH₂), 54.0 (CH₂), 57.7 (CH₂), 122.4 (CH), 126.9 (CH), 127.8 (CH), 128.2 (CH), 128.6 (CH), 128.8 (CH), 129.1 (CH), 134.9 (C), 139.2 (C), 146.0 (C) ppm. HRMS (ESI+): calcd for C₂₄H₂₅N₄⁺ 369.2074 [M + H]⁺; found 369.2072.

1,1′-((5-Methyl-1,3-phenylene)bis(methylene))bis(4-phenyl-1H-1,2,3-triazole) (4j)

The general procedure at 60 °C for 30 min between 1,3-bis(bromomethyl)-5-methylbenzene 1d (139 mg, 0.50 mmol), sodium azide (2, 66 mg, 1.01 mmol), ethynylbenzene 3a (115 μL, 1.05 mmol), and CuIL₁PPh₃ (3.3 mg, 1 mol %) afforded compound 4j as a white solid (173 mg, 85%); mp 159–160 °C (ref⁵¹, 145–146 °C). ¹H NMR (400 MHz, CDCl₃): δ = 2.31 (s, 3H), 5.50 (s, 4H), 7.06–7.08 (m, 3H), 7.31 (t, J = 7.4 Hz, 2H), 7.39 (t, J = 7.4 Hz, 4H), 7.68 (s, 2H), 7.79 (d, J = 7.4 Hz, 4H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 21.3 (CH₃), 53.9 (CH₂), 119.7 (CH), 124.6 (CH), 125.8 (CH), 128.3 (CH), 128.9 (CH), 129.1 (CH), 130.5 (C), 135.9 (C), 140.3 (C), 148.4 (C) ppm. HRMS (ESI+): calcd for C₂₅H₂₃N₆⁺ 407.1979 [M + H]⁺; found 407.1980. These NMR data matched previously reported data.⁵¹

1,1′-((5-Methyl-1,3-phenylene)bis(methylene))bis(4-(4-fluorophenyl)-1H-1,2,3-triazole) (4k)

The general procedure at 60 °C for 30 min between 1,3-bis(bromomethyl)-5-methylbenzene 1d (136 mg, 0.49 mmol), sodium azide (2, 66 mg, 1.01 mmol), 1-ethynyl-4-fluorobenzene (3c, 122 mg, 1.02 mmol), and CuIL₁PPh₃ (3.3 mg, 1 mol %) afforded compound 4k as a white solid (171 mg, 79%); mp 221–222 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 2.28 (s, 3H), 5.59 (s, 4H), 7.11–7.17 (m, 3H), 7.26 (t, J = 8.8 Hz, 4H), 7.84–7.88 (m, 4H), 8.59 (s, 2H) ppm. ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ = 20.8 (CH₃), 52.7 (CH₂), 115.8 (CH, ²J_C–F = 22.2 Hz), 121.4 (CH), 124.6 (CH), 127.1 (CH, ³J_C–F = 8.0 Hz), 127.2 (C), 128.3 (CH), 136.5 (C), 138.8 (C), 145.8 (C), 161.7 (C, ¹J_C–F = 245.4 Hz) ppm. HRMS (ESI+): calcd for C₂₅H₂₁F₂N₆⁺ 443.1790 [M + H]⁺; found 443.1792.

2,6-bis((4-Phenyl-1H-1,2,3-triazol-1-yl)methyl)pyridine (4l)

The general procedure at 60 °C for 30 min between 2,6-bis(chloromethyl)pyridine 1e (88 mg, 0.50 mmol), sodium azide (2, 68 mg, 1.05 mmol), ethynylbenzene (3a, 112 μL, 1.02 mmol), and CuIL₁PPh₃ (3.3 mg, 1 mol %mol %) afforded compound 4l as a white solid (157 mg, 80%); mp 165 °C (ref⁵², 159–161 °C). ¹H NMR (400 MHz, CDCl₃): δ = 5.67 (s, 4H), 7.18 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.38 (t, J = 7.4 Hz, 4H), 7.68 (t, J = 8.0 Hz, 1H), 7.79 (d, J = 7.4 Hz, 4H), 7.87 (s, 2H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 55.3 (CH₂), 120.3 (CH), 122.0 (CH), 125.8 (CH), 128.3 (CH), 128.9 (CH), 130.4 (C), 138.8 (CH), 148.3 (C), 154.7 (C) ppm. HRMS (ESI+): calcd for C₂₃H₂₀N₇⁺ 394.1775 [M + H]⁺; found 394.1778. These NMR data matched previously reported data.⁵²

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c04592.

• Copies of ¹H and ¹³C{¹H} NMR spectra for all compounds and crystallographic details of Cu(I) complexes (PDF)

• CuIL₁PPh₃ (CIF)

• [CuI(PPh3)]₄ (CIF)

Accession Codes

CCDC 2010534 (CuIL₁PPh) and 201053 ([CuIPPh₃]₄) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge through www.ccdc.cam.ac.uk/data_request/cif or by emailing data_request@ccdc.cam.ac.uk or contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

The authors declare no competing financial interest.