Synthesis of Mono- and Binuclear Cu(II) Complexes Bearing

Article pubs.acs.org/Organometallics

Synthesis of Mono- and Binuclear Cu(II) Complexes Bearing Unsymmetrical Bipyridine−Pyrazole−Amine Ligand and Their Applications in Azide−Alkyne Cycloaddition Wenjing Ye,* Xiao Xiao, Lan Wang, Shicheng Hou, and Chun Hu* Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang, 110016 Liaoning, China S Supporting Information *

ABSTRACT: Mono- and binuclear Cu(II) complexes bearing an unsymmetrical bipyridine−pyrazole−amine ligand were synthesized and characterized using X-ray diffraction. The mononuclear complex could be converted to the corresponding binuclear complexes under basic conditions due to the lability of the pyrazolyl N−H. Both complexes proved to be effective catalysts for azide−alkyne cycloaddition to form triazoles, with the binuclear complex exhibiting higher catalytic activity than the corresponding mononuclear one. The binuclear complex was effective at catalyst loadings as low as 0.0125 mol %, making it one of the most active catalysts for this reaction to date. Therefore, this catalyst was applied in the synthesis of potentially biologically active molecules. At 0.1−0.3 mol % catalyst loading, three precursors of Sorafenib analogs were synthesized in excellent yields. A one-pot variant of the reaction, generating the azide in situ, could also be performed using the binuclear complex as the catalyst. The transition metal complex bearing an unsymmetrical ligand may exhibit excellent catalytic activity, which represents a direction for developing new highly active catalysts.

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INTRODUCTION Development of ligands bearing donors other than phosphorus has attracted much recent attention in the fields of coordination chemistry, homogeneous catalysis, and organic synthesis. As an alternative to phosphorus ligands, N-heterocyclic ligands have many potential advantages: (i) ease of synthesis, (ii) higher stability and lower toxicity, and (iii) excellent σ-donor properties.1 Over the last few decades, a large number of Nheterocyclic ligand scaffolds with symmetrical backbones have been developed, and their potential applications have been demonstrated. For example, NNN tridentate pincer ligands such as PyBOX,2 2,6-bis-(imino)pyridines,3 and terpyridines,4 as well as “scorpionate” N3-tripodal neutral ligands such as hydrotris(1-pyrazolyl)methane HC(pz)3, Tpm,5 and poly(pyrazolyl) borates.6 In contrast, a series of unsymmetrical ligands (termed “hemilabile ligands” by Jeffrey and Rauchfuss in 1979)7 comprised substitutionally labile and substitutionally inert groups have also been reported. The inert group in the ligand is anchored to the transition metal center, stabilizing the catalyst. The labile group is always a weakly coordinating one, being easily dissociated or converted. This can help generate a vacant site on the transition metal center for substrate binding. Furthermore, the wider variability in the structure of unsymmetrical ligands allows for a wider scope for altering the electronic and steric environment around the catalytic metal center. These characteristics have enabled hemilabile ligands to © 2017 American Chemical Society

remarkably improve the effectiveness of various organometallic catalysts. Unsymmetrical systems utilizing a variety of heteroatoms and different coordinating abilities are known.8 For example, P/S,9 P/O,10 P/N,11 N/O,12 and C/S13 systems bearing a dissociable group have been employed in catalytic applications. Nevertheless, the use of unsymmetrical Nheterocyclic ligands bearing a convertible group in catalytic organic chemistry is still an underexplored area.14 We have been interested in developing unsymmetrical Nheterocyclic ligands, in particular, ligands bearing a convertible group, and the corresponding highly effective catalyst system for application in homogeneous catalysis. Recently, we have reported versatile unsymmetrical pyridyl-based NNN ligands bearing a convertible group (either benzimidazolyl or pyrazolyl) and their exceptionally active Ru(II) complexes for transfer hydrogenation (TH) and asymmetric transfer hydrogenation (ATH) of ketones (Scheme 1).15 Mechanistic studies demonstrate that the NH moiety of the benzimidazolyl and pyrazolyl moieties is convertible in the presence of a base such as NEt3, resulting in excellent catalytic activity of the Ru(II)− NNN complexes due to easy in situ generation of coordinatively unsaturated 16-electron Ru(II) precatalysts. Received: February 28, 2017 Published: May 12, 2017 2116

DOI: 10.1021/acs.organomet.7b00154 Organometallics 2017, 36, 2116−2125

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Organometallics

bipyridine−pyrazole−amine ligand, which showed excellent catalytic activity for the 1,3-dipolar cycloaddition reaction between alkynes and azides (Scheme 2).22 Herein, we report the continued development of this system for the CuAAC reaction. Both mononuclear Cu complex 3 and binuclear Cu complex 4 were successfully synthesized and used as catalysts for the 1,3-dipolar cycloaddition reaction between alkynes and azides.

Scheme 1. Ligands Bearing an NH Group

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RESULTS AND DISCUSSION Synthesis and Spectroscopic Characterization. Bipyridine−pyrazole−amine ligand 1 was synthesized using our previously reported methods.22 This ligand provides a convenient scaffold for the synthesis of mononuclear and binuclear Cu complexes due to the presence of the NH group in the pyrazole. At first, Cu(CH3CN)4PF6 was chosen as the Cu precursor and reacted with ligand 1 under N2 to obtain a Cu(I) complex. However, the resulting product was easily oxidized by air and ultimately Cu(II) complex 2 was generated.22,23 Herein, we directly employed a Cu(II) precursor, such as CuBr2, which was reacted with ligand 1 in MeOH under air at room temperature for 16 h, affording mononuclear Cu(II) complex 3 in 48% yield after recrystallization from MeOH−hexane−Et2O (1:1:3) using the “layering” approach. As we expected, mononuclear complex 3 could be converted to binuclear complex 4 in the presence of NEt3 via loss of a HBr molecule, due to the existence of a convertible NH in the pyrazolyl group. After two recrystallizations from MeOH−hexane−Et2O (1:1:3) using the “layering” approach, crystals of complex 4 suitable for X-ray diffraction were obtained in 76% yield. Complexes 3 and 4 were air-stable, but attempts to determine their structure by 1 H and 13C NMR spectroscopy were unsuccessful, possibly due to the paramagnetic nature of the Cu(II) center.23 The molecular structures of complexes 3 and 4 were confirmed by X-ray crystallographic studies, as shown in Figures 1 and 2, respectively. Mononuclear complex 3 adopts a square-pyramidal geometry with a tridentate κ3-coordination mode of the N-heterocyclic ligand, which coordinates to the Cu(II) center through an amino nitrogen and two pyridyl nitrogen atoms. The bond to the amine N atom (2.075(11) Å) is longer than those to the pyridine N atoms (1.973(11) and 1.976(10) Å), denoting a weaker interaction with the Cu(II) center. The fourth and fifth coordination sites are occupied by two bromide anions. The Br1 anion occupies the apex of the

The Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction between alkynes and azides (CuAAC) for constructing triazole cycles is the archetypal “click chemistry”, which was reported independently by Sharpless16 and Meldal.17 This triazole synthesis has been widely applied in medicinal, bioorganic, and materials chemistry, as well as many other research areas over the past decade.18 Over the past 10 years, numerous efficient catalytic methods have been developed for accelerating the catalytic process and decreasing the amount of metal catalyst needed, for example, the use of ligands or direct use of air- and moisture-stable Cu(I) salts as catalysts.19 The most widely applied catalytic systems for CuAAC are based on symmetrical polydentate nitrogen ligands such as the tris(benzyltriazolylmethyl) amine (TBTA) system introduced by Sharpless and co-workers19j (Scheme 1). However, Finn and co-workers20 recently found that hybrid tripodal ligands bearing combinations of different heterocyclic fragments (mixed ligands) are more active than their symmetrical analogs. Very recently, Semakin and co-workers21 reported that “mixed” oxime−triazole ligands, TzβOx2 and Tz2βOx, demonstrated an approximately 10-fold enhanced acceleration effect in comparison to that shown by TBTA, using 0.1 mol % of the Cu/L catalytic system (Scheme 1). In a recent preliminary communication, we explored the activity of binuclear Cu complex 2, bearing an unsymmetrical Scheme 2. Synthesis of Mono- and Binuclear Cu Complexesa

a

Reaction conditions: (i) Cu(CH3CN)4PF6, MeOH, rt, in air, 16 h, 71%.22 (ii) CuBr2, MeOH, rt, in air, 16 h, 48%. (iii) 1.5 equiv of NEt3, MeOH, rt, in air, 20 h, 76%. 2117


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Organometallics

In dinuclear bis-(pyrazolato)-bridged Cu(II) compound 4, the geometry around each Cu(II) center is distorted trigonalbipyramidal (τ = 0.89) with a crystallographically imposed inversion symmetry passing through the two bridging pyrazolato groups. The axial positions of the trigonal bipyramid are occupied by amino nitrogen N3 and nitrogen N2A in the pyrazolato bridge of the other ligand with an N2A−Cu1−N3 angle of 177.5(2)°. N1, N4, and N5 atoms occupy three vertexes of the basal plane, in which the bond angles around the Cu1 atom are 110.8(2), 117.5(2), and 124.4(2)°, respectively. The Cu(II)−nitrogen bond lengths range from 1.942(5) to 2.141(6) Å, with the shortest bond being between Cu1 and N2A of the pyrazolato, attributed to its covalent nature. Performance of Mononuclear Complex 3 and Binuclear Complex 4 in CuAAC Reactions. In our recent research, binuclear Cu complex 2 was applied as a catalyst for the 1,3-dipolar cycloaddition reaction between alkynes and azides. As reported in the preliminary communication, screening of reaction conditions revealed that MeOH was the most suitable solvent and that the ultimate catalyst loading leading to complete conversion of the reactants was 0.1 mol %, with a reaction time of 16 h (Table 1, entry 1).22 Considering

Figure 1. Molecular structure of 3. Selected bond lengths (Å) and angles (deg): Br(1)−Cu(1), 2.614(2); Br(2)−Cu(1), 2.429(2); Cu(1)−N(2), 1.973(11); Cu(1)−N(3), 1.976(10); Cu(1)−N(1), 2.075(11); N(2)−Cu(1)−N(3), 163.1(5); N(2)−Cu(1)−N(1), 80.6(5); N(3)−Cu(1)−N(1), 82.7(5); N(2)−Cu(1)−Br(2), 94.1(3); N(3)−Cu(1)−Br(2), 98.1(3); N(1)−Cu(1)−Br(2), 145.6(3); N(2)−Cu(1)−Br(1), 96.9(4); N(3)−Cu(1)−Br(1), 91.3(4); N(1)−Cu(1)−Br(1), 109.6(3); Br(2)−Cu(1)−Br(1), 104.74(8).

Table 1. Optimization of the Reaction Conditions for CuAACa

entry 1b,c 2 3 4 5 6 7d 8e 9

Figure 2. Molecular structure of 4 with the H2O molecule and bromide anion omitted for clarity. Selected bond lengths (Å) and angles (deg): Cu(1)−N(2)#1, 1.942(5); Cu(1)−N(1), 2.009(5); Cu(1)−N(3), 2.067(5); Cu(1)−N(4), 2.093(5); Cu(1)−N(5), 2.141(6); N(2)#1−Cu(1)−N(1), 98.9(2); N(2)#1−Cu(1)−N(3), 177.5(2); N(1)−Cu(1)−N(3), 82.0(2); N(2)#1−Cu(1)−N(4), 100.5(2); N(1)−Cu(1)−N(4), 124.4(2); N(3)−Cu(1)−N(4), 80.8(2); N(2)#1−Cu(1)−N(5), 97.6(2); N(1)−Cu(1)−N(5), 117.5(2); N(3)−Cu(1)−N(5), 80.0(2); N(4)−Cu(1)−N(5), 110.8(2).

cat. (mol %) 2 3 3 3 3 3 3 3 4

(0.1) (0.05) (0.025) (0.025) (0.01) (0.025) (0.025) (0.025) (0.0125)

NaAsc (mol %) 1 1 1 1 1 1 1 1

NEt3 (mol %)

1 1 1 1 1

isolated yield (%) 99 93 27 99 29 N.R. 17 92 98

a

Reaction conditions: 1.0 mmol of phenylacetylene, 1.0 mmol of benzyl azide, 1 mL of MeOH, N2, 25 °C, 16 h. bRef 22. cMeOH = 1.5 mL. dUnder air. et-BuOH/H2O (1:1) as solvents.

the structural similarity of complexes 2−4, we chose MeOH as the solvent for exploring the application of complexes 3 and 4. Mononuclear complex 3 demonstrated slightly better activity than that of binuclear complex 2, reaching 93% yield at 0.05 mol % catalyst loading (Table 1, entry 2). When the amount of catalyst 3 was decreased to 0.025 mol %, only 27% yield was obtained (Table 1, entry 3). However, we were delighted to see a dramatic acceleration upon addition of 1 mol % NEt3, giving 99% yield (Table 1, entry 4). Further decreasing the catalyst loading led to the incomplete conversion of the reactants, giving 29% yield with 0.01 mol % catalyst loading (Table 1, entry 5). The cycloaddition reaction did not take place in the absence of sodium L-ascorbate, indicating that the active species was a Cu(I) complex (Table 1, entry 6).26 The reaction was also performed under air, and the triazole product was obtained in an isolated yield of only 17%, possibly because the resulting active Cu(I) species was oxidized to inactive Cu(I) species by air (Table 1, entry 7). When the solvent was changed to tBuOH/H2O, the reaction between phenylacetylene and benzyl

square-pyramid, and the four vertexes of the base are occupied by Br1, N1, N2, and N3 atoms. The angles around the Cu(II) atom in the basal plane vary from 80.6(5) to 98.1(3)°, indicating a distorted square-pyramid geometry, which can be quantitatively identified using the parameter τ = 0.29, as defined by Addison et al. (τ = 1 for the trigonal bipyramid and 0 for the square pyramid).24 Surprisingly, the N4 atom of the pyrazolyl is not coordinated to the Cu(II) center but remains dissociated. Changing the reaction temperature from room temperature to reflux, we still obtained complex 3 with an uncoordinated pyrazolyl arm, rather than the desired complex in which the bipyridine−pyrazole−amine ligand presented a κ4-coordination mode. Nicasio and co-workers recently reported a similar Cu(I) complex bearing a tris-(pyrazolyl-methyl)amine ligand, which in the solid-state structure presented a κ3-coordination mode with an uncoordinated pyrazolyl arm.25 However, in solution, it existed in an equilibrium between κ3- and κ4-coordinate species. 2118


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Organometallics Table 2. 1,3-Dipolar Cycloaddition Reaction of Various Alkynes and Azides Catalyzed by Mononuclear Complex 3a

a

Reaction conditions: 1.0 mmol of alkynes, 1.0 mmol of benzyl azide, cat. 3 (0.025 mol %), 1 mol % sodium L-ascorbate, 1 mol % NEt3, 1.0 mL of MeOH, N2, 25 °C, 16 h. b0.05 mol % cat. 3.

azide afforded the triazole product in 92% yield (Table 1, entry 8). Binuclear Cu complex 4 showed the best catalytic activity at half the catalyst loading (0.0125 mol %), with the cycloaddition reaction giving the desired product in 98% yield (Table 1, entry 9). It exhibited higher activity than did complex 2, possibly due to the effect of Br− anion. Bertrand recently demonstrated the Janus-face role of the anion ligand in the CuAAC catalytic process.27 It is worth mentioning that when complexes 3 and 4 were used as catalysts the amount of the solvent varied from 1.5 to 1 mL as these two complexes exhibited greater solubility in MeOH than did complex 2 (Table 1, entries 2−9).

With the optimized conditions in hand, the scope of the cycloaddition was explored (Tables 2 and 3). A broad variety of alkynes (5a−q) and azides (6a−h), both equipped with various functional moieties such as arenes with electron-withdrawing or -donating substituents, heterocycles, alcohols, alkanes, and esters were successfully employed. As expected, most alkynes reacted with the azides to give nearly quantitative yields of the 1,4-disubstituted triazole products. The reactions of fluorosubstituted phenylacetylenes (5b−d) with benzyl azide 6a afforded the corresponding 1,4-disubstituted triazoles in 97, 97, and 99% yields, respectively (Table 2, entries 2−4). Similar 2119


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propargyl alcohol 5m with benzyl azide 6a afforded corresponding 1,4-disubstituted triazole 7m in 97% yield (Table 2, entry 13). Interestingly, the more hindered alcohol, 5n, also exhibited excellent reactivity, giving 1,4-disubstituted triazole 7n in 96% yield (Table 2, entry 14). Aliphatic alkynes 5o and 5p displayed moderate reactivity, both giving yields of 71% with 0.05 mol % catalyst loading (Table 2, entries 15 and 16). Pericàs et al. have previously demonstrated that these two substrates exhibit lower reactivity and require longer reaction times for complete conversion using their catalyst in this reaction.19e Unfortunately, the reaction of ethyl propiolate 5q with benzyl azide 6a gave a complex mixture of products, and we were unable to isolate the expected products, perhaps because of the presence of NEt3 (Table 2, entry 17). The reaction of the internal alkyne diphenylacetylene with benzyl azide was also investigated: No products were obtained, and the reactants were recycled. CuAAC reactions between phenylacetylene 5a and fluoro- or methyl-substituted azides (6b and 6c) were also investigated at 0.05 mol % catalyst loading, affording corresponding 1,4-disubstituted triazoles 7q and 7r in 99% yield (Table 2, entries 18 and 19). To further explore the scope of the reaction, a range of aryl-substituted azides (6d−h) were reacted with phenylacetylene 5a under the optimized conditions. However, these azides were generally less reactive than benzyl azide 6a, and the reactions required a higher catalyst loading of 0.05 mol % for completion. Nevertheless, the various phenyl azides, bearing electron-withdrawing or -donating substituents (6d−g), could be converted to the corresponding triazole products in 96−99% yields (Table 2, entries 20−23). m-Nitrophenyl azide 6h displayed excellent reactivity, giving corresponding triazole 7w in an isolated yield of 99% (Table 2, entry 24). To investigate the effect of NEt3 upon this CuAAC reaction, we added NEt3 to a methanolic solution of mononuclear complex 3 and successfully obtained the binuclear complex 4, which possessed the same cationic structure as complex 2. Next, we examined the catalytic activity of binuclear complex 4 for the CuAAC reaction with half the catalyst loading based on complex 3 for maintaining a constant amount of Cu, because complex 4 was a dimer of complex 3. As we expected, complex 4 showed catalytic activity nearly identical with that of the combined system of mononuclear complex 3 and NEt3 for most substrates (Table 3, entries 1−4 and 7−9, and Table 2, entries 1, 7, 11, 14, and 19−21). We hypothesized that complex 3 can be considered as a precursor to complex 4 and that their similar catalytic activity is presumably due to the in situ formation of 4 from 3 under basic conditions (NEt3 as a base).15b Using complex 4 as a catalyst, aliphatic and estersubstituted alkynes (5o, 5p, and 5q) exhibited better reactivity than that with complex 3, giving 95, 85, and 65% yields, respectively (Table 3, entries 5, 6, and 10). In the combined system of catalyst 3 and NEt3, the basic conditions may cause some side reactions, leading to lower yields of the desired triazole products and producing other unknown products. Surprisingly, binuclear complex 4 displayed higher catalytic activity than binuclear complex 2 and mononuclear complex 3 in the CuAAC reaction, promoting the quantitative formation of triazole products 7 from most substrates at extremely low loading (0.0125−0.025 mol %). To expand the application of this highly effective catalyst, it was also used for the synthesis of complicated molecules, as shown in Scheme 3. Diazotization of amine 11 (an intermediate in the synthesis of Sorafenib (BAY 43−9006), the first oral multikinase inhibitor), 28 and

Table 3. 1,3-Dipolar Cycloaddition Reaction of Various Alkynes and Azides Catalyzed by Binuclear Complex 4a

a

Reaction conditions: 1.0 mmol of alkynes, 1.0 mmol of benzyl azide, cat. 4 (0.025 mol %), sodium L-ascorbate 1 mol %, MeOH 1.0 mL, N2, 25 °C, 16 h. b0.0125 mol % Cat. 4.

results were obtained with chloro- and bromo-substituted phenylacetylene substrates (5e−g), affording 1,4-disubstituted triazoles in 97−99% yields (Table 2, entries 5−7). The reactions of phenylacetylenes bearing electron-donating substituents (5h−j) with benzyl azide 6a also gave satisfactory results, producing 1,4-disubstituted triazoles in 97−98% yields (Table 2, entries 8−10). Heterocycle-substituted alkynes 5k and 5l also showed excellent reactivity and were completely converted to the desired triazole products in 99% yields but required a catalyst loading of 0.05 mol % (Table 2, entries 11 and 12). The presence of unprotected OH groups in the substrates did not inhibit catalyst 3; this is not entirely surprising as similar behavior was previously observed with complex 2.22 Using 0.05 mol % catalyst, the reaction of 2120


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loading at 25 °C, giving the corresponding triazole 7a in 52% yield in 16 h. After the amount of catalyst and reaction temperature were increased, triazole 7a was obtained in 97% isolated yield within 24 h (Table 4, entry 1). Therefore, using 0.1 mol % catalyst loading at 50 °C for 24 h as the optimal reaction conditions, the reactions of a wide variety of alkynes equipped with various functional moieties (like arenes, heterocycles, alcohols, and alkanes) with benzyl bromide and sodium azide have been developed, giving the corresponding triazole products in good-to-excellent yields. Halogenated phenylacetylenes showed slightly lower reactivity, giving the corresponding triazoles in 89−94% yields (Table 4, entries 2− 7). The reaction of methyl-substituted phenylacetylenes 5h and 5i afforded the corresponding triazoles in 90 and 92% yields, respectively (Table 4, entries 8 and 9). This methodology could be extended to heterocyclic alkynes such as commercially available 2-ethynylpyridine 5k and 2-ethynylthiophene 5l to afford the desirable heterocycle-functionalized triazoles in 90 and 89% yields, respectively (Table 4, entries 10 and 11). This one-pot method was also applicable to alkyne substrates with an alcohol group. The reaction of alcoholic alkynes 5m and 5n afforded triazoles 7m and 7n in 92% yield (Table 4, entries 12 and 13). Unsurprisingly, alkyl-substituted alkyne 5o showed only moderate reactivity, giving triazole 7o in 65% yield (Table 4, entry 14). The scope of the benzyl reaction partner was also investigated. Electron-poor p-fluorobenzyl bromide 13b and electron-rich p-methylbenzyl bromide 13c reacted smoothly to afford corresponding triazoles 7q and 7r in 97 and 90% yields, respectively (Table 4, entries 15 and 16). The results obtained above for the one-pot method show that the established protocol was very effective for most alkynes, although the results were not as good as those for direct cycloaddition between alkynes and azides. The NaBr formed from the reaction of the starting bromide with NaN3 might inhibit the cycloaddition reaction.33 As far as we know, these results represent one of the lowest catalyst loadings used so far for this three-component transformation.39 Mechanistic Considerations. Initially, a stepwise catalytic cycle was proposed, which proceeded via a six-membered copper-containing intermediate.16,40 Further studies demonstrated a second-order dependence on catalyst concentration for both ligand-free41 and most ligand-containing42 CuAAC reactions. Compared to the already reported monocopper intermediate, the dinuclear Cu(I) intermediate participates in the rate-determining step, leading to a further drop in the activation barrier.43 Several binuclear Cu complex catalysts showed superior catalytic activity.19g,k,44 Bertrand et al. reported that although mono- and bis-copper complexes promote the CuAAC reaction the pathway involving the dinuclear species was kinetically favored, and they successfully isolated a hitherto never-mentioned bis(metalated) triazole complex.45 On the basis of these findings and the results of catalytic activities, we propose a bimetallic mechanism for CuAAC reactions catalyzed by 3 or 4 (Scheme 4). In the presence of NEt3, the catalytic activity of mononuclear complex 3 is equivalent to that of the binuclear complex 4 (see Tables 2 vs 3); therefore, the CuAAC reaction can be initiated directly from 4 or in situ generated 4 by deprotonation of 2 equiv of 3. Next, as in most Cu(II) catalytic systems, 4 is reduced in situ to the active Cu(I) species A by sodium L-ascorbate, but we were unable to confirm the structure of A due to its extreme lability in air. The starting alkyne then reacts with A to form binuclear acetylide−copper complex B, displacing one of the pyridyl coordinating groups

Scheme 3. Application of Catalyst 4 in the Synthesis of Complicated Moleculesa

a

Conditions: (i) HCl/NaNO2, 1.2 equiv of NaN3, EtOAc, rt, 3 h; (ii) 0.1 mol % cat. 4 for 8 and 9, 0.3 mol % cat. 4 for 10, Na L-ascorbate, MeOH, 25 °C, 16 h.

subsequent substitution with sodium azide (NaN3) gave azide 6i. With 0.1 mol % catalyst loading at 25 °C, the cycloaddition reaction of 6i with alkynes 5a and 5g gave corresponding triazole products 8 and 9 in 96 and 94% isolated yields in 16 h, respectively. It is worth mentioning that triazole 9 was obtained in high purity and nearly quantitative yield after a simple filtration and methanol wash, without the use of column chromatography, due to its extremely poor solubility in methanol. Since resulting triazole 9 bears a bromo substituent, it is primed for further functionalization. Ester analog 6j was synthesized following the same method as amide 6i and was then reacted with phenylacetylene 5a to give corresponding triazole 10 in 91% isolated yield. This reaction required a higher catalyst loading of 0.3 mol %. From these precursors, we hope to synthesize a range of Sorafenib analogs and assess their bioactivity. Performance of Binuclear Complex 4 in One-Pot CuAAC Reactions. Organic azides, especially those of low molecular weight, are known to be generally unstable and potentially explosive. In order to avoid the isolation and purification processes for organic azides in these types of cycloaddition reaction, one-pot synthesis of triazoles were developed, using aromatic or alkyl halides and sodium azide for direct cycloaddition with alkynes.29 Various copper catalysts such as Cu2O,30 CuI,31 CuSO4,32 CuBr(PPh3)3,33 and other heterogeneous catalysts34 have been used in this reaction. Furthermore, one-pot triazole preparation from N-sulfonylaziridines,35 amines,36 boronic acids,37 or diaryliodonium salts38 has also been performed via in situ preparation of azides. Considering the extraordinary catalytic activity of binuclear complex 4 in the CuAAC reaction, we decided to evaluate our catalytic system for the one-pot CuAAC reaction of alkyl halides, sodium azide, and alkynes, as shown in Table 4. First, we completed the one-pot reaction of phenylacetylene with benzyl bromide and sodium azide with 0.05 mol % catalyst 2121


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Table 4. One-Pot 1,3-Dipolar Cycloaddition of Various Alkynes and Benzyl Bromides with Sodium Azide, Catalyzed by the Binuclear Complex 4a

a Reaction conditions: 1.0 mmol of alkynes, 1.0 mmol of benzyl bromide, 1.0 mmol of NaN3, cat. 4 (0.1 mol %), 2 mol % sodium L-ascorbate, 1.0 mL of MeOH, N2, 50 °C, 24 h.

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CONCLUSION In conclusion, we have developed two novel copper complexes bearing an unsymmetrical bipyridine−pyrazole−amine ligand, mononuclear complex 3 and binuclear complex 4, and applied them as catalysts for the CuAAC reaction. Owing to the convertibility of NH in the pyrazolyl group of ligand 1, complex 4 could be obtained through the loss of HBr from complex 3 in the presence of triethylamine. Binuclear complex 4 showed a higher catalytic activity than that of mononuclear complex 3; however, when triethylamine was added to the reaction system, complex 3 exhibited catalytic activity equivalent with that of complex 4, suggesting that binuclear complex 4 forms in situ by deprotonation of 3. Using sodium L-ascorbate as a reducing agent and MeOH as a solvent, 1,3-dipolar cycloaddition reactions between various alkynes and azides were catalyzed by complexes 3 and 4, and the corresponding 1,4-disubstituted triazoles were obtained in good-to-excellent yields. Binuclear complex 4 exhibited surprisingly high catalytic activity and could promote the CuAAC reaction at a catalyst loading as low as 0.0125 mol %, which is one of the lowest catalyst loadings used in this reaction to date. As is widely known, click chemistry is often applied in medicinal, bioorganic, and

(L). The subsequent nucleophilic attack of the acetylide carbon to the “external” nitrogen atom of the azide generates coppertriazolide E through one of two possible transition states, C or D. In transition state C, the acetylide and the azide are coordinated to the same Cu atom (Cub) and the second Cu atom (Cua) π-coordinates to the acetylide, leading to a further drop in the activation barrier.43b−d However, because Cua and Cub are bridged by two pyrazolato groups, the distance between them may not be close enough to allow both of them to interact with the same acetylide. Thus, it is also possible that the reaction proceeds through transition state D, in which one Cu center binds the acetylide fragment and the other Cu center binds the azide fragment, synergistically providing a cyclic transition state for the reaction between the terminal azide nitrogen and the positively charged secondary carbon of the acetylide. This possibility has been suggested by Bock et al.43a and Meldal et al.,26 and is supported by mechanistic studies performed by Rodionov et al.41 In the last step, protonation of E and recoordination of ligand L afford the triazole product and regenerate the active catalyst A. Hence, we cannot rule out that ligand L is exchanged with the acetylide. 2122


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Organometallics Scheme 4. Proposed Mechanisma

N-((1H-Pyrazol-3-yl)methyl)-1-(pyridin-2-yl)-N-(pyridin-2ylmethyl)methanamine·CuBr2 (3). To a MeOH (10 mL) solution of ligand 1 (2.15 mmol, 0.600 g) was added with stirring an equimolar amount of CuBr2 (2.15 mmol, 0.480 g) in MeOH (10 mL). The solution was stirred at rt for 24 h in air. The final green solution was concentrated under reduced pressure to 5 mL and then layered with hexane (5 mL) and Et2O (15 mL) for recrystallization at 2−8 °C to give 3 as green crystals (0.519 g, 48% yield), which were suitable for Xray diffraction. Mp: >200 °C dec. HRMS Calcd for C16H18CuBr2N5 M: 499.9147; Found for C16H18CuBr2N5 M: 499.9141. N-((1H-Pyrazol-3-yl)methyl)-1-(pyridin-2-yl)-N-(pyridin-2ylmethyl)methanamine·CuBr (4). To a MeOH (20 mL) solution of complex 3 (0.46 mmol, 0.233 g) was added with stirring the base NEt3 (1.5 equiv, 0.7 mmol, 0.070 g). The solution was stirred at rt for 20 h in air. The final green solution was concentrated under reduced pressure to 5 mL and then layered with hexane (5 mL) and Et2O (15 mL) for recrystallization at 2−8 °C to give green crystals as the target complexes and white crystals as NEt3·HBr together. Then, the green crystals were picked from the mixture and recrystallize through layering method (V(MeOH):V(hexane):V(Et2O) = 1:1:3) for a second time. Complex 4 was obtained as green crystals suitable for X-ray diffraction (0.150 g, 76% yield). Mp: >200 °C dec. HRMS Calcd for C 32 H 32 BrCu 2 N 10 [M − Br − ] + : 761.0587; Found for C32H32BrCu2N10 [M − Br−]+: 761.0590. 4-(4-Azidophenoxy)-N-methylpicolinamide (6i).48 To a 0 °C solution of 4-(4-aminophenoxy)-N-methyl-picolinamide (11) (0.520 g, 2.14 mmol) in EtOAc (10 mL) was added concentrated hydrochloride (0.9 mL), followed by addition of a solution of NaNO2 (0.177 g, 2.6 mmol) in 2.5 mL of H2O consecutive dropwise addition over a period of 10 min with stirring. After the mixture was stirred for a further 1 h, a solution of NaN3 (0.169 g, 2.6 mmol) in H2O (2.5 mL) was added to the above reaction mixture with stirring. The reaction mixture was warmed to room temperature and stirred for 3 h. The aqueous layer was separated, and the organic layer was washed with water (5 mL × 4) up to pH = 6. Then, the solution was dried over Na2SO4, filtered, and concentrated in vacuo to give 6i (0.336 g, 61%, brown solid), which was used for the next step without further purification. 1H NMR (600 MHz, d6-DMSO) δ 8.77 (d, 1H, J = 4.3 Hz, NH), 8.51 (d, 1H, J = 5.5 Hz, aromatic CH), 7.39 (d, 2H, J = 2.0 Hz, aromatic CH), 7.29−7.23 (m, 4H, aromatic CH), 7.15−7.14 (m, 1H, aromatic CH), 2.79 (d, 3H, J = 4.7 Hz, CH3). Methyl 4-(4-Azidophenoxy)picolinate (6j). To a 0 °C solution of methyl 4-(4 minophenoxy)-picolinate (12)49 (0.560 g, 2.29 mmol) in EtOAc (50 mL) was added concentrated hydrochloride (0.9 mL), followed by addition of a solution of NaNO2 (0.190 g, 2.75 mmol) in 2.5 mL of H2O by consecutive dropwise addition over a period of 10 min with stirring. After the mixture was stirred for a further 1 h, a solution of NaN3 (0.179 g, 2.75 mmol) in H2O (2.5 mL) was added to the above reaction mixture with stirring. The reaction mixture was warmed to room temperature and stirred for 3 h. The aqueous layer was extracted by using ethyl acetate (15 mL × 3), and then the organic layers were combined, washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 6j (0.600 g, 97%, gray solid), which was used for the next step without further purification. Mp: 108−110 °C. 1H NMR (600 MHz, d6-DMSO) δ 8.64 (d, 1H, J = 4.8 Hz, aromatic CH), 7.51 (s, 1H, aromatic CH), 7.31−7.26 (m, 5H, aromatic CH), 3.87 (s, 3H, CH3). 13C NMR (150 MHz, d6-DMSO) δ 166.3, 163.7, 150.5, 149.9, 148.0, 137.4, 122.6, 121.3, 115.3, 112.9, 53.0. HRMS Calcd for C13H10N4O3 M: 270.0753; Found for C13H10N4O3 M: 270.0755. General Procedure for 3-Catalyzed 1,3-Dipolar Cycloaddition Reactions. Under N2 atmosphere, a mixture of alkyne (1.0 mmol), azide (1.0 mmol), Na ascorbate (0.01 mmol, 1 mol %), NEt3 (0.01 mmol, 1 mol %), and 0.25 × 10−3 M solution of catalyst 3 in MeOH (1.0 mL, 0.025 mol %) was stirred in a 10 mL Schlenk tube at 25 °C for 16 h. Evaporation of the solvents followed by purification by short column chromatography on silica gel provided the desired 1,4disubstituted triazole product. The unreacted alkyne and azide were first eluted out with petroleum ether (PE), and the pure 1,4-

a

L: pyridyl or tertiary amino group. L′: pyrazolato group. Partially coordinating groups are omitted for clarity.

materials chemistry. Low catalyst loading could significantly reduce the negative impact of residual metals. Furthermore, this method was found to be equally effective and straightforward for the preparation of potentially biologically active compounds. Several new triazoles, which are precursors to Sorafenib analogs, were obtained in 91−96% isolated yields through a CuAAC reaction catalyzed by binuclear complex 4. A one-pot synthesis of 1,4-disubstituted triazoles via a threecomponent reaction between terminal alkynes, organic bromides, and sodium azide could be also achieved using binuclear complex 4 as a catalyst to give the desired products in good-to-excellent yields. The isolation and purification of organic azides were avoided in this procedure, as they were prepared in situ. Transition metal complexes bearing unsymmetrical ligands can exhibit excellent catalytic activity, which represents a direction for developing new highly active catalysts. Future work will focus on developing the application of this catalyst to the synthesis of a series of potentially biologically active compounds bearing a triazole group, and the bioactivity of these compounds.

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EXPERIMENTAL SECTION

General Remarks. 1H and 13C{1H} NMR spectra were recorded on a Bruker DRX-600 spectrometer and all chemical shift values refer to TMS = 0.00 ppm, CDCl3 ((1H), 7.26 ppm; (13C), 77.16 ppm), or d6-DMSO ((1H), 2.50 ppm; (13C), 39.52 ppm). HRMS analysis was carried out on an Agilent 6500 Q-TOF mass spectrometer (Version Q-TOF B.05.01). All the chemical reagents were purchased from commercial sources. All the solvents were purified according to the routine methods before used. Azides 6b,c and 6d−h were respectively prepared through methods reported for the syntheses of 6a46 and 6d47 and subsequently applied in the 1,3-dipolar cycloaddition reaction. (Caution: Low-molecular-weight carbon azides used in this study are potentially explosive. Appropriate protection measures (lab coat, gloves, and goggles) should always be used when handling these compounds.) 2123


Article

Organometallics disubstituted triazole product was then obtained by elution with 1:3 PE/ethyl acetate. General Procedure for 4-Catalyzed 1,3-Dipolar Cycloaddition Reactions. Under N2 atmosphere, a mixture of alkyne (1.0 mmol), azide (1.0 mmol), Na ascorbate (0.01 mmol, 1 mol %), and 0.125 × 10−3 M solution of catalyst 4 in MeOH (1.0 mL, 0.0125 mol %) was stirred in a 10 mL Schlenk tube at 25 °C for 16 h. Evaporation of the solvents followed by purification by short column chromatography on silica gel provided the desired 1,4-disubstituted triazole product. The unreacted alkyne and azide were first eluted out with PE, and the pure 1,4-disubstituted triazole product was then obtained by elution with 1:3 PE/ethyl acetate or pure ethyl acetate. General Procedure for One-Pot Cu-Catalyzed 1,3-Dipolar Cycloaddition Reactions. Under N2 atmosphere, a mixture of alkyne (1.0 mmol), benzyl bromide (1.0 mmol), NaN3 (1.0 mmol), Na ascorbate (0.02 mmol, 2 mol %), and 1.0 × 10−3 M solution of catalyst 4 in MeOH (1.0 mL, 0.1 mol %) was stirred in a 10 mL Schlenk tube at 50 °C for 24 h. Evaporation of the solvents followed by purification by short column chromatography on silica gel provided the desired 1,4-disubstituted triazole product. The unreacted alkyne and azide were first eluted out with PE, and the pure 1,4-disubstituted triazole product was then obtained by elution with 3:1 PE/ethyl acetate. N-Methyl-4-(4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenoxy)picolina-mide (8). Yield: 96%, white powder. Mp: 208−209 °C. 1H NMR (600 MHz, d6-DMSO) δ 9.34 (s, 1H, triazole-H), 8.81 (d, 1H, J = 4.6 Hz, NH), 8.57 (d, 1H, J = 5.5 Hz, aromatic CH), 8.10 (d, 2H, J = 8.8 Hz, aromatic CH), 7.96 (d, 2H, J = 7.4 Hz, aromatic CH), 7.52− 7.50 (m, 5H, aromatic CH), 7.40 (t, 1H, J = 7.4 Hz, aromatic CH), 7.26 (dd, 1H, J1 = 5.3 Hz, J2 = 2.3 Hz, aromatic CH), 2.81 (d, 3H, J = 4.7 Hz, CH3). 13C NMR (150 MHz, d6-DMSO) δ 165.6, 164.2, 153.8, 153.1, 151.1, 147.9, 134.6, 130.7, 129.5, 128.8, 125.8, 122.9, 120.3, 115.0, 109.8, 26.50. HRMS Calcd for C21H17N5O2 M: 371.1382; Found for C21H17N5O2 M: 371.1386. 4-(4-(4-(4-Bromophenyl)-1H-1,2,3-triazol-1-yl)phenoxy)-Nmethylpicolinamide (9). Under N2 atmosphere, a mixture of alkyne (0.5 mmol), 6i (0.5 mmol), Na ascorbate (0.1 mmol, 2 mol %), and 0.25 × 10−3 M solution of catalyst 4 in MeOH (1.0 mL, 0.025 mol %) was stirred in a 10 mL Schlenk tube at 25 °C for 16 h. The product was obtain by filtration of the reaction mixture and washing sequentially with MeOH (2 mL × 4). The result precipitate was dried under vacuum to afford desired product 9 as white solid (0.211 g, 94%, white solid). Mp: 259−260 °C. 1H NMR (600 MHz, d6DMSO) δ 9.40 (s, 1H, triazole-H), 8.81 (d, 1H, J = 4.7 Hz, NH), 8.58 (d, 1H, J = 5.6 Hz, aromatic CH), 8.09 (d, 2H, J = 8.9 Hz, aromatic CH), 7.92 (d, 2H, J = 8.4 Hz, aromatic CH), 7.74 (d, 2H, J = 8.4 Hz, aromatic CH), 7.54 (d, 2H, J = 8.9 Hz, aromatic CH), 7.49 (d, 1H, J = 2.4 Hz, aromatic CH), 7.28 (dd, 1H, J1 = 5.5 Hz, J2 = 2.5 Hz, aromatic CH), 2.80 (d, 3H, J = 4.8 Hz, CH3). 13C NMR (150 MHz, d6-DMSO) δ 165.1, 163.7, 153.4, 150.7, 146.3, 134.0, 132.0, 129.5, 128.7, 127.3, 125.4, 122.4, 121.3, 120.3, 117.0, 114.6, 109.3, 99.5, 26.0. HRMS Calcd for C21H16BrN5O2 M: 449.0487; Found for C21H16BrN5O2 M: 449.0488. Methyl 4-(4-(4-Phenyl-1H-1,2,3-triazol-1-yl)pheno-xy)picolinate (10). Yield: 91%, white solid. Mp: 186−188 °C. 1H NMR (600 MHz, d6-DMSO) δ 9.34 (s, 1H, triazole-H), 8.64 (d, 1H, J = 5.5 Hz, aromatic CH), 8.10 (d, 2H, J = 8.7 Hz, aromatic CH), 7.96 (d, 2H, J = 7.9 Hz, aromatic CH), 7.55−7.50 (m, 5H, aromatic CH), 7.40 (t, 1H, J = 7.3 Hz, aromatic CH), 7.30 (dd, 1H, J1 = 5.5 Hz, J2 = 2.4 Hz, aromatic CH), 3.86 (s, 3H, CH3). 13C NMR (150 MHz, d6DMSO) δ 164.8, 164.6, 153.2, 151.9, 149.7, 147.4, 134.1, 130.2, 129.0, 128.3, 125.3, 122.3, 122.2, 119.8, 115.4, 112.9, 52.6. HRMS Calcd for C21H16N4O3 M: 372.1222; Found for C21H16N4O3 M: 372.1224.

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Details of X-ray crystallography for 3 and 4, experimental procedures, analytical data of triazholes, and copies of NMR spectra (PDF) Accession Codes

CCDC 1444291 and 1444292 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Wenjing Ye: 0000-0002-1222-8489 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the NNSFC (21502120), China Postdoctoral Science Foundation (2013M541254), and Scientific Research Fund of Liaoning Provincial Education Department (L2015525).

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REFERENCES

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.7b00154. 2124


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