Highly efficient click reaction on water catalyzed by a ruthenium complex

Abstract

The highly efficient click reaction between terminal alkynes and azides has been achieved on water using ruthenium complex RuH₂(CO)(PPh₃)₃ as the catalyst, and the catalyst loading was decreased to 0.2 mol% on water from 5 mol% in organic solvent. The RuH₂(CO)(PPh₃)₃/H₂O system also catalyzed the one-pot click reaction of bromides, sodium azide and alkynes; in this process, azides formed in situ and then underwent a click reaction with alkynes. In both aqueous processes, 1,4-disubstituted 1,2,3-triazoles were obtained in 50–89% yield with high regioselectivity.

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Introduction

Water, which is unquestionably cheap, safe, non-toxic and readily available,¹ is becoming an increasingly popular medium for organic reactions.² Ever since Breslow adapted the Diels–Alder reaction to water,³ extraordinary advances have been made in performing organic chemistry in aqueous media.^2,4 Chemists who make use of water as a solvent are often confronted with problems such as the antagonistic nature of water toward nucleophilic organic compounds⁵ and the limited solubility of the organic components. However, in some cases, using water as a solvent can accelerate reaction rates and enhance yield and selectivity compared to the same reaction in organic solvent,⁶ even when the reactants are only sparingly soluble or insoluble in water. Various factors have been proposed to explain how water can cause these enhancements. These factors include the hydrophobic effect,⁷ hydrogen bonding,^8,9 and the method used to mix reactants in water.¹⁰ Another advantage of conducting reactions in aqueous solvent is that it facilitates the design of one-pot consecutive and multicomponent reactions (MCRs), which tend to be more environmentally friendly and atom-economical than conventional organic syntheses.¹¹

One of the most ingenious examples of “click chemistry”¹² is the copper-catalyzed Huisgen 1,3-dipolar cycloaddition of azides and alkynes (CuAAC), discovered by Meldal¹³ and Sharpless.¹⁴ This click reaction is the most direct route to 1,4-disubstituted 1,2,3-triazoles,¹⁵ which are applied widely across various fields, including biological science,¹⁶ synthetic organic chemistry,¹⁷ medicinal chemistry¹⁸ and material chemistry.¹⁹ Therefore, tremendous attention has been given to develop new protocols for the synthesis of various 1,2,3-triazoles.²⁰ The ruthenium-catalyzed azide–alkyne cycloaddition reaction (RuAAC) relying on pentamethylcyclopentadienyl ruthenium chloride catalysts has been reported to give 1,5-disubstituted-1,2,3-triazole with high regioselectivity.²¹

In an effort to adapt the RuAAC reaction to aqueous solvent, we took advantage of a ruthenium hydride complex, RuH₂(CO)(PPh₃)₃, which we previously showed to catalyze the click reaction in organic solvent to afford 1,4-disubstituted-1,2,3-triazole with high regioselectivity.²² Here we report that the RuH₂(CO)(PPh₃)₃-catalyzed click reaction on water led to much higher reactivity and proceeded efficiently at catalyst loadings as low as 0.2 mol%. The synthetic usefulness of this catalytic system was further demonstrated by achieving the one-pot multicomponent cycloaddition of bromides, sodium azide and alkynes.

Results and discussion

We began our investigation of ruthenium-catalyzed cycloaddition using benzyl azide (1a) and phenylacetylene (2a) as the model substrates, and the resulting reaction mixture was analyzed by ¹H NMR using PhSiMe₃ as the internal standard (Table 1). Initially, 1a and 2a were heated on water at 80 °C for 2 h in the presence of RuH₂(CO)(PPh₃)₃; this led to 100% conversion and 86% yield of 1,4-disubstituted 1,2,3-triazole 3a with 100% regioselectivity (entry 1). Encouraged by these results, we optimized the reaction by adding phase transformation catalyst (PTC), which can solubilize organic materials or form emulsions with them on water. In the presence of Bu₄NBr, catalyst loading could be reduced from 5 mol% to 0.2 mol% while maintaining a 100% conversion and generating the 1,4-disubstituted 1,2,3-triazole 3a in >86% yield with 100% regioselectivity (entries 2–6). Lowering catalyst loading below 0.1 mol% led to incomplete substrate conversion (entry 7).

Table 1 RuH₂(CO)(PPh₃)₃-catalyzed click reaction of 1a and 2a on water under various conditions^a

Entry	S/C	PTC	Conv.^b (%)	Yield^c (%)
a Reactions were performed in sealed tubes containing 1a (0.5 mmol), 2a (1.0 mmol), PTC (0.025 mmol) and water (0.5 mL) under N2 for 2 hours, unless noted otherwise.b Conversions were estimated by integrating the area under the peaks for triazole and unreacted azide in ^1H NMR spectra.c Based on the integrated area of the peak for unreacted azide (1a) in ^1H NMR spectra, using PhSiMe3 as the internal standard.d 1a (0.5 mmol) and 2a (0.6 mmol) were used.e Isolated yield is shown in parentheses.
1	20	—	100	86
2	20	Bu4NBr	100	95
3	50	Bu4NBr	100	95
4	100	Bu4NBr	100	94
5	200	Bu4NBr	100	86
6	500	Bu4NBr	100	92
7	1000	Bu4NBr	69	63
8	500	CTAB	100	95
9	500	Bu4NI	99	87
10	500	PEG2000	66	28
11	500	Cyclodextrin	64	47
12	500	Tween-80	54	37
13	500	—	74	57
14^d	500	Bu4NBr	100	94 (89)^e

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Various other PTCs were then tested. Although CTAB gave 100% conversion and generated the desired 1,4-product in 95% yield, it also generated the 1,5-product as by-product in 3% yield (entry 8). Bu₄NI, PEG2000, cyclodextrin or Tween-80 were inferior to Bu₄NBr, giving either lower conversion or yields of products and selectivity (entries 9–12). Eliminating the PTC entirely led to poor conversion and yield (entry 13). Changing the reactant ratio (1a : 2a) from 1 : 2 to 1 : 1.2 gave the desired 1,4-product in 89% isolated yield (entry 14).

Encouraged by the reaction efficiency, we examined its scope using the following optimized conditions: 1a : 2a, 1 : 1.2; RuH₂(CO)(PPh₃)₃, 0.2 mol%; Bu₄NBr, 5 mol%; H₂O, 0.5 mL; 80 °C; 2 h. These conditions worked well for a variety of terminal alkynes and azides (Table 2). All reactions of benzyl azide 1a with aromatic alkynes containing electron-donating or electron-withdrawing groups proceeded smoothly to afford 1,4-substituted triazole products 3b–3g in 71–88% yield. The results illustrate that the electronic properties of substituents on the benzene ring of alkynes does not appreciably affect the aqueous click reaction. Ferrocenylacetylene and alkyl alkyne were also effective in this ruthenium complex-catalyzed click reaction, producing the corresponding triazoles 3h and 3i in respective isolated yields of 80% and 82%. The reaction also proceeded with 3-ethynylpyridine, giving 3j in 62% yield, while using 2-ethynylthiophene gave 3k in 52% yield.

Table 2 RuH₂(CO)(PPh₃)₃-catalyzed cycloaddition of various alkynes and organic azides on water^ab

a Reaction conditions: azide (0.5 mmol), alkyne (0.6 mmol), RuH₂CO(PPh₃)₃ (0.001 mmol), Bu₄NBr (0.025 mmol), 80 °C, 2 h, 0.5 mL of water.b Isolated yields are reported.

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Next we examined the substrate scope of organic azides. Benzyl azide bearing methyl, methoxy, or fluoride groups underwent this transformation efficiently, giving products 3l–3n in 86–89% isolated yield. Alkyl organic azides also reacted efficiently, giving the desired products 3o–3q with high isolated yields of 76–87%. The hydroxyl-functionalized azide was a good reaction partner, generating triazole 3r with phenylacetylene in 82% yield. The reaction tolerated a substitution of the benzylic methylene of benzyl azide with a methyl group, leading to formation of 3s in 89% yield. This suggests that the reaction is insensitive to steric hindrance of the azide.

Based on the above results, the RuH₂(CO)(PPh₃)₃-catalyzed click reactions on water gave yields similar to those of the corresponding reactions in organic solvent. At the same time, the use of aqueous solvent allowed us to reduce the catalyst loading from 5 mol% to 0.2 mol%.

Multicomponent reactions (MCRs) involve connecting three or more starting materials in a single synthetic operation with high atom economy and bond-forming efficiency.²³ This allows the construction of high molecular diversity and complexity in a relatively rapid and straightforward manner.²⁴ One-pot MCRs often involve shorter reaction times and higher overall yields than multi-step syntheses, thereby reducing energy and manpower requirements.²⁵ Given the desirability of eliminating the need to store or manipulate organic azides, we envisaged a one-pot MCR involving an alkyne, sodium azide and bromide. Our plan was to generate organic azides in situ from suitable precursors, which would then undergo RuH₂(CO)(PPh₃)₃-catalyzed azide–alkyne cycloaddition on water, thereby forming 1,2,3-triazoles. In this one-pot approach, we wished to avoid the need for interim purification of potentially unstable organic azide intermediates.

First, we screened various conditions for this one-pot MCR by taking as our model reaction the standard three-component click reaction of benzyl bromide and sodium azide with phenylacetylene. As we envisaged, the ruthenium complex RuH₂(CO)(PPh₃)₃ was amenable to this one-pot MCR on water, displaying high activity towards this multicomponent reaction to generate 1,4-disubstituted 1,2,3-triazoles from simple substrates. After screening various catalyst loadings and PTCs, we obtained 3a in 84% isolated yield in the presence of 2 mol% catalyst after incubating the reaction for 2 h at 80 °C (Table 3).

Table 3 Optimization of conditions for the RuH₂(CO)(PPh₃)₃-catalyzed, one-pot click reaction of benzyl bromide, sodium azide, and phenylacetylene on water^a

Entry	S/C	PTC	Conv.^b (%)	Yield^c (%)
a Reactions were performed in sealed tubes containing benzyl bromide (0.5 mmol), sodium azide (0.55 mmol), phenylacetylene (0.6 mmol), PTC (0.025 mmol) and water (0.5 mL) under N2 for 2 hours.b Conversion rates were estimated by integrating the area under the peaks for triazole and unreacted benzyl bromide in ^1H NMR spectra.c Based on the integrated area of the peak for unreacted benzyl bromide in ^1H NMR spectra, using PhSiMe3 as the internal standard.d Isolated yield is shown in parentheses.
1	20	Bu4NI	100	63
2	50	Bu4NI	100	79 (84)^d
3	100	Bu4NI	71	49
4	200	Bu4NI	22	22
5	1000	Bu4NI	21	22
6	50	Bu4NBr	75	54
7	50	—	81	42

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Then we tested the scope of this one-pot RuAAC MCR (Table 4). A broad range of aromatic alkynes containing electron-donating or electron-withdrawing groups and heterocyclic alkynes were compatible with this reaction, affording the desired products 3a–3k in 50–88% isolated yield. Various bromides including aromatic and alkyl substrates were also compatible with the reaction, providing 71–88% yields of the desired products 3l–3s. These results demonstrate that the one-pot, three-component click reactions were comparable to the click reactions of alkynes and azides, although the one-pot format required increasing the catalyst loading of RuH₂(CO)(PPh₃)₃ to 2 mol%.

Table 4 RuH₂(CO)(PPh₃)₃-catalyzed, one-pot click reaction of various bromides, sodium azide, and various alkynes^a

a The reaction was carried out using bromide (0.5 mmol), sodium azide (0.55 mmol), alkyne (0.6 mmol) and Bu₄NI (0.025 mmol) in the presence of RuH₂CO(PPh₃)₃ (0.01 mmol) on water (0.5 mL) at 80 °C for 2 h.

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Conclusions

Using water as the reaction medium, we have developed a highly efficient RuH₂(CO)(PPh₃)₃-catalyzed click reaction between terminal alkynes and organic azides to afford various 1,4-disubstituted triazoles in good to excellent yield. Catalyst loading (0.2 mol%) was much lower than that required in organic solvent (5 mol%). This catalytic system proved suitable for one-pot, three-component reactions of bromides, sodium azide, and alkynes, eliminating the need for interim purification of in situ-generated organic azides as well as significantly improving overall efficiency. We believe this protocol will offer a good option as an efficient click reaction and contribute substantially to the rapid growth in applications of click chemistry.

Experimental section

General information

All manipulations were carried out under a nitrogen atmosphere using standard Schlenk techniques, unless otherwise stated. RuH₂(CO)(PPh₃)₃ was prepared as described.²⁶ Freshly distilled water was used as solvent. Alkynes and other chemicals were purchased from Aldrich. Mass spectra were collected on an API QSTAR XLSystem (ESI) or GCT Premier™ Mass Spectrometer (CI). ¹H and ¹³C{¹H} NMR spectra were collected on a Bruker AV 400 MHz NMR spectrometer. ¹H and ¹³C NMR chemical shifts were determined relative to TMS or residue of deuterium solvents.

Typical procedure for the RuH₂(CO)(PPh₃)₃-catalyzed click reaction of various terminal alkynes and organic azides on water with low catalyst loading. To a mixture of azide (0.5 mmol), alkyne (0.6 mmol), and H₂O (0.5 mL) were added catalyst RuH₂(CO)(PPh₃)₃ (0.001 mmol) and phase transformation catalyst (PTC) Bu₄NBr (0.025 mmol). The resulting solution was stirred at 80 °C for 2 h. Then the reaction mixture was extracted three times with 1 mL CHCl₃. The organic phases were combined, the solvent was evaporated under reduced pressure, and the residue was subjected to flash column chromatography on silica gel to afford the desired product. All the compounds reported here are known, except for 3i and 3r (see ESI†).

Typical procedure for RuH₂(CO)(PPh₃)₃-catalyzed one-pot click reaction of benzyl bromide, sodium azide, and phenylacetylene on water. To a mixture of bromide (0.5 mmol), sodium azide (0.55 mmol), alkyne (0.6 mmol) and H₂O (0.5 mL) were added catalyst RuH₂(CO)(PPh₃)₃ (0.01 mmol) and PTC Bu₄NI (0.025 mmol). The resulting solution was stirred at 80 °C for 2 h. Then the reaction mixture was extracted three times with 1 mL CHCl₃. The organic phases were combined, the solvent was evaporated under reduced pressure, and the residue was subjected to flash column chromatography on silica gel to afford the desired product. All the compounds reported here are known (see ESI†), except for 3i and 3r.
1-Benzyl-4-(3-phenyl-propyl)-1H-1,2,3-triazole (3i). Mp: 60–62.5 °C; ¹H NMR (400 MHz, CDCl₃, 25 °C) δ 7.34–7.37 (m, 3H), 7.24–7.26 (m, 4H), 7.15–7.19 (m, 4H), 5.49 (s, 2H), 2.64–2.74 (dt, 4H), 1.94–2.02 (m, 2H); ¹³C NMR (100.6 MHz, CDCl₃, 25 °C) δ 148.4, 141.9, 135.0, 129.1, 128.6, 128.5, 128.4, 128.0, 125.9, 120.7, 54.0, 35.4, 31.3, 25.3; HRMS (ESI, TOF) calcd for C₁₈H₂₀N₃ [M + H]⁺ 278.1562, found 278.1567.
4-(4-Phenyl-1,2,3-triazol-1-yl)-butan-1-ol (3r). Mp: 88–90 °C; ¹H NMR (400 MHz, CDCl₃, 25 °C) δ 7.82 (m, 2H), 7.78 (s, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 4.47 (t, J = 7.1 Hz, 2H), 3.71 (t, J = 6.1 Hz, 2H), 2.04–2.12 (m, 2H), 1.60–1.66 (m, 3H); ¹³C NMR (100.6 MHz, CDCl₃, 25 °C) δ 147.8, 130.6, 128.9, 128.2, 125.7, 119.6, 61.9, 50.2, 29.3, 27.0; HRMS (ESI, TOF) calcd for C₁₂H₁₆N₃O [M + H]⁺ 218.1288, found 218.1287.

Acknowledgements

This work was supported by NSFC/China, NCET (NCET-13-0798), the Basic Research Program of the Shanghai Committee of Sci. & Tech. (Project no. 13NM1400802), and the Fundamental Research Funds for the Central Universities.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Analytical data for all known products (melting point, ¹H and ¹³C NMR, MS), copies of ¹H NMR spectra of all products, copies of ¹³C NMR spectra of 3i and 3r. See DOI: 10.1039/c4ra12960a

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