A four-coordinate Cu(I)– N -heterocyclic carbene complex: Synthesis,structure,properties,and application in amination for the synthesis of 1-(2- N -heteroaryl)-1 H -pyrazoles

Abstract

A new luminescent, cationic, heteroleptic, four-coordinate Cu(I)–N-heterocyclic carbene complex [Cu(Br-Pyim)(POP)](PF₆) is successfully prepared and characterized, where Br-Pyim and POP are 1-(6-bromopyridin-2-yl)imidazole-3-benzyl-2-ylidene and bis[2-(diphenylphosphino)phenyl]ether, respectively. Its detailed structure is determined by single-crystal X-ray analysis. It exists as a crystalline powder at room temperature and exhibits bright yellow-green emission. The use of the Cu(I)–N-heterocyclic carbene complex as a catalyst for amination reactions is also investigated and is found to be very efficient for the amination of 2-N-heteroaryl chlorides with pyrazoles, giving the desired substituted 1-(2-N-heteroaryl)-1H-pyrazoles in good yields.

Introduction

N-Arylpyrazoles are important intermediates used in the synthesis of many agrochemicals, pharmaceuticals, and functional materials.^1,2 The N-arylpyrazole structural unit can be obtained by several synthetic methods, among which transition-metal-catalyzed amination of aryl halides is one of the most direct and powerful.^3–5 In contrast to expensive catalysts such as palladium and rhodium complexes, low-cost copper catalysts are attracting considerable attention due to their potential use in industrial and practical applications.^6–9 Many copper/ligand systems have been reported, most of which utilize CuI as the catalyst and other Cu sources (e.g. Cu₂O, CuCl). However, the copper/ligand catalytic processes have not been well-determined; in particular, the structures of the Cu(I) pre-catalysts are rarely investigated.^8,9

It is well-known that N-heterocyclic carbenes (NHCs) have strong σ-donating and modest π-accepting abilities, which make them widely used as ligands in catalysis and materials science.^10–13 Recently, Thompson’s group reported luminescent Cu(I)−NHC complexes, and these complexes exhibited moderate-to-high emission efficiency.^14,15 We have also reported several cationic, heteroleptic, four-coordinate Cu(I)−NHC complexes with high emission efficiency and tunable emission wavelengths by modifying the structure of NHC ligands.^16,17 In view of these findings and our continuing interest in the synthesis of NHC complexes as well as their application in coupling reactions,^18,19 we were interested to investigate whether the obtained Cu(I)–NHC complexes were active for aminations. Thus, we prepared a new photoluminescence Cu(I)–NHC complex and examined its catalytic activity in the amination of pyrazoles.

Results and discussion

Synthesis and structure

The new four-coordinate Cu(I)–NHC complex 1 was prepared using the method reported by our group (Scheme 1)^16,17 and characterized by elemental analysis, mass spectroscopy (MS), and ¹H, ³¹P, and ¹³C NMR spectroscopy. It is very stable to air and moisture in a solid state at room temperature. The nuclear magnetic resonance (NMR) spectrum of 1 was consistent with the proposed structure, and the signal for the carbene carbon atom was observed at 158.7 ppm in the ¹³C NMR spectrum. Furthermore, its detailed structure was confirmed by X-ray diffraction analysis. Single crystals were obtained through slow evaporation of an acetone solution at room temperature. The crystal structure of 1 is shown in Figure. 1. The Cu in the complex is in a typical distorted tetrahedral environment and is bonded to two P atoms of POP, a C atom, and the N atom of the NHC (Br-Pyim) ligand. The imidazolylidene ring and the pyridine ring of the NHC ligand are nearly coplanar and the dihedral angle is 6.4°. The bond lengths of Cu−C, Cu−N, and Cu(I)−P are similar to those of reported related four-coordinate Cu complexes.^14–17

Scheme 1.

Synthesis of four-coordinate Cu(I)–NHC complex 1.

Figure 1.

X-ray crystal structure of 1. H atoms, CH₃COCH₃, and PF⁶⁻ are omitted for clarity. Selected bond lengths (Å) and angles (°) are as follows: Cu–N1 2.309(3), Cu–C8 1.964(3), Cu–P1 2.2566(9), Cu–P2 2.2693(10), and N1–Cu–C8 77.55(13), C8–Cu–P1 122.89(10), P1–Cu–P2 114.41(3), and P2–Cu–N1 121.96(8).

Absorption and emission

In CH₂Cl₂ solution, complex 1 exhibits three absorption bands as shown in Figure. 2. The intense high-energy absorption bands at 232 and 280 nm are ligand-centered (LC) π-π* transitions. The weaker absorption band at 340 nm can be assigned to the charge transfer (CT) transitions, which should include metal-to-ligand charge transfer (MLCT) and ligand-to-ligand (LLCT) transitions, according to previous reports.^16,17 It does not show luminescence in organic solutions at room temperature; ²⁰ however, as a crystalline powder it shows intense yellow-green emission with a photoluminescence (PL) spectrum at 555 nm at room temperature (298 K). The absolute PL quantum yield and emission lifetime were measured to be 26% and 76.0 μs, respectively. At a low temperature of 77 K, the PL peak of 1 appears at 570 nm which is red-shifted by about 16 nm compared to that acquired at 298 K. In addition, the emission lifetime was measured to be 231.3 μs at 77 K, which increased by a factor of 3 compared to that acquired at 298 K (Figure 2, inset). These results imply that emission of this complex at room temperature is thermally activated delayed fluorescence (TADF).

Figure 2.

Absorption and photoluminescence (PL) spectra of 1. The inset is the emission decay behavior of 1 in the solid state at 298 and 77 K.

Amination

1-(2-N-Heteroaryl)-1H-pyrazole derivatives as N,N ligands have found widespread applications in the fields of supramolecular chemistry and crystal engineering. Coupling reactions of N-heteroaryl halides have become one of the most valuable synthetic processes for N-heterocyclic compounds.^21,22 For example, 2-chloro pyridines and 2-chloropyrimidines are important coupling partners in these reactions.^23–25 However, the amination of 2-N-heteroaryl halides with pyrazoles has been relatively less reported.^26,27 So, we have investigated the catalytic activity of complex 1 for the N-arylation of 2-N-heteroaryl chlorides with pyrazoles.

Initially, the use of complex 1 as a catalyst for the coupling reaction of 2-chloro-5-methylpyridine with 1H-pyrazole was examined. Using 0.5 mol% of 1 in dioxane at 110 °C for 12 h provided the desired product 2. The results from this study are summarized in Table 1. After screening a variety of bases (entries 1–6), KO^tBu was found to give the best result, while NaO^tBu gave a moderate yield. A survey of solvents indicated that dioxane was much better than other solvents such as tetrahydrofuran (THF), dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) (entries 7–10). Toluene also afforded a good yield. In addition, CuI/Br-HPyimPF₆ and CuI/POP were poorly active under the same reaction conditions (entries 11 and 12). However, CuI/Br-HPyimPF₆/POP generated the product in a 72% yield, showing a synergistic ligand effect between the NHC and POP ligands in the amination (entry 13).^28–31

Table 1.

Optimization of the reaction conditions for the amination of 2-chloro-5-methylpyridine with 1H-pyrazole. ^a

Entry	Base	Solvent	Catalyst (mol%)	Yield (%) b
1	Na2CO3	Dioxane	1 (0.5)	28
2	K2CO3	Dioxane	1 (0.5)	42
3	KOH	Dioxane	1 (0.5)	53
4	K3PO4	Dioxane	1 (0.5)	36
5	NaOtBu	Dioxane	1 (0.5)	75
6	KOtBu	Dioxane	1 (0.5)	91
7	KOtBu	Toluene	1 (0.5)	86
8	KOtBu	THF	1 (0.5)	49
9	KOtBu	DMF	1 (0.5)	37
10	KOtBu	DMSO	1 (0.5)	54
11	KOtBu	Dioxane	CuI (0.5)/Br-HPyimPF6 (1)	38
12	KOtBu	Dioxane	CuI (0.5)/POP (1)	25
13	KOtBu	Dioxane	CuI (0.5)/Br-HPyimPF6 (1)/POP (1)	72

THF: tetrahydrofuran; DMF: dimethylformamide; DMSO: dimethyl sulfoxide.

a

Reaction conditions: 2-chloro-5-methylpyridine (1.0 mmol), 1H-pyrazole (1.1 mmol), base (2.0 mmol), solvent (3 mL), 110 °C, 12 h.

b

Isolated yield.

Compared with 1H-pyrazole, 3,5-dimethyl-1H-pyrazole showed no deleterious effect on these reactions. Under the optimized reaction conditions, the amination of 3,5-dimethyl-1H-pyrazole with 2-chloro-5-methylpyridine gave product 3 in a good yield (89%). In subsequent experiments, the coupling of a variety of electronically and structurally 2-N-heteroaryl chlorides with pyrazoles catalyzed by complex 1 was carried out (Table 2). Products 4a,b were obtained from 2-chloropyridine in good yields (92% and 90%). For electron-rich 2-chloropyridine derivatives, the yields of the coupled products 5 and 6 were 84%–91%. As expected, the coupling reactions of activated 2-chloropyridine derivatives gave the products 7–10 in excellent yields (90%–96%). Finally, we investigated the couplings of 2-chloropyrimidine and 2-chloropyrazine and found them to be efficient coupling partners in this system giving products 11 and 12 in good yields.

Table 2.

Aminations of 2-N-heteroaryl chlorides with pyrazoles catalyzed by 1. ^a

a

Reaction conditions: 2-N-heteroaryl chloride (1.0 mmol), pyrazole (1.1 mmol), 1 (0.5 mol%), KO^tBu (2.0 mmol), dioxane (3 mL), 110 °C, 12 h.

Conclusion

A new photoluminescent four-coordinate Cu–NHC complex has been synthesized and characterized. The complex demonstrates efficient TADF in the solid state at room temperature. In addition, we have developed an efficient method for the amination of N-heteroaryl chlorides with pyrazoles catalyzed by this Cu–NHC complex. This protocol provides an efficient access to a variety of substituted 1-(2-N-heteroaryl) -1H- pyrazoles.

Experimental

Materials and equipment

Solvents were dried and freshly distilled prior to use. All other chemicals were commercially available, expect for 1-(6-bromopyridin-2-yl)-3-benzylimidazolium hexafluorophosphate (Br-HPyimPF₆), which was prepared according to the published procedure.^16,17 Elemental analyses were determined with a Carlo Erba 1160 Elemental Analyzer. Mass spectra were measured on a LC-MSD-Trap-XCT instrument. ¹H, ³¹P, and ¹³C NMR spectra were recorded on a Bruker DPX-400 spectrometer (400, 162, and 100 MHz, respectively) with tetramethylsilane (TMS) as an internal standard. The absorption and PL spectra were recorded on a Hitachi U-3010 UV-Vis spectrophotometer and a Hitachi F-4500 fluorescence spectrophotometer.

Synthesis of [Cu(Br-Pyim)(POP)](PF₆) 1

Under an N₂ atmosphere, Br-HPyimPF₆ (1 mmol), copper powder (1.2 mmol), and bis[2-(diphenylphosphino)phenyl]ether (POP, 1 mmol) were stirred in CH₃CN (10 mL) at 70 C overnight. After cooling, the resulting mixture was filtered, and then the filtrate was collected and evaporated under vacuum. The residue was dissolved in dichloromethane/ethanol, and the product was obtained as yellow crystals by slow evaporation of the solvent. Yield: 63%. ¹H NMR (400 MHz, CD₃CN): δ 7.76–7.85 (m, 2H), 7.61–7.68 (m, 1H), 7.34–7.49 (m, 16H), 7.09–7.15 (m, 6H), 7.00–7.04 (m, 6H), 6.85–6.98 (m, 5H), 6.49–6.52 (s, 2H), 4.55 (s, 2H). ¹³C NMR (100 MHz, CD₃CN): δ 158.7, 151.6, 143.1, 141.7, 136.7, 134.6, 133.0, 131.1, 131.2, 129.8, 129.7, 129.6, 128.8, 128.0, 125.9, 125.8, 124.0, 118.3, 55.0. ³¹P NMR (162 MHz, CD₃CN): δ −9.9 (s), −144.2 (q). MS-ESI⁺: m/z = 914.1 (M–PF₆)⁺. Anal. Calcd for C₅₁H₄₀BrCuF₆N₃OP₃: C, 57.7; H, 3.8; N, 4.0. Found: C, 57.9; H, 3.5; N, 4.2%.

General procedure for the amination

In a Schlenk tube, a mixture of the catalyst 1 (0.5 mol%), 2-N-heteroaryl chloride (1.0 mmol), pyrazole (1.1 mmol), and KO^tBu (2.0 mmol) in dioxane (3 mL) was evacuated and charged with nitrogen. The reaction mixture was heated at 110 °C for 12 h. After being cooled and quenched with water, the mixture was extracted with CH₂Cl₂. The solvent was evaporated and the resulting residue was purified by flash chromatography on silica gel. The products 4a, b, ³² 5a, ³³ 5b, ³⁴ 7a, ³⁵ 11a, ³⁶ 11b, ³⁷ and 12a ³⁸ are known compounds and characterized by comparison of their data with those reported in the literature. Other products were characterized by elemental analysis, MS, and ¹H and ¹³C NMR.

5-Methyl-2-(1H-pyrazol-1-yl)pyridine (2):

¹H NMR (400 MHz, CDCl₃): δ 8.52 (d, J = 2.4 Hz, 1H), 8.22 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 6.45 (d, J = 1.6 Hz, 1H), 2.35 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 149.8, 148.0, 141.8, 139.4, 131.0, 126.9, 112.1, 107.6, 18.0. MS-ESI⁺: m/z = 159.1. Anal. Calcd for C₉H₉N₃: C, 67.9; H, 5.7; N, 26.4. Found: C, 68.2; H, 5.3; N, 26.9%.

5-Methyl-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine (3):

¹H NMR (400 MHz, CDCl₃): δ 8.26 (s, 1H), 7.70 (d, J = 6.8 Hz, 1H), 7.60 (d, J = 6.8 Hz, 1H), 5.99 (s, 1H), 2.36 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 149.8, 146.1, 139.4, 131.0, 126.9, 112.1, 110.8, 107.6, 29.8, 15.7, 13.8. MS-ESI⁺: m/z = 187.1. Anal. Calcd for C₁₁H₁₃N₃: C, 70.6; H, 7.0; N, 22.4. Found: C, 71.0; H, 6.7; N, 22.6%.

2-Methoxy-6-(1H-pyrazol-1-yl)pyridine (6a):

¹H NMR (400 MHz, CDCl₃): δ 8.53 (s, 1H), 7.72 (m, 2H), 7.53 (d, J = 7.6 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 1.2 Hz, 1H), 3.99 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 163.3, 149.6, 142.0, 141.1, 127.1, 107.8, 107.4, 103.9, 53.6. MS-ESI⁺: m/z = 175.1. Anal. Calcd for C₉H₉N₃O: C, 61.7; H, 5.2; N, 24.0. Found: C, 61.9; H, 4.9; N, 24.3%.

2-Methoxy-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine (6b):

¹H NMR (400 MHz, CDCl₃): δ 7.66 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 5.99 (s, 1H), 3.93 (s, 3H), 2.69 (s, 3H), 2.29 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 162.8, 151.6, 149.9, 141.3, 140.7, 109.1, 107.1, 107.0, 53.9, 15.0, 13.8. MS-ESI⁺: m/z = 203.1. Anal. Calcd for C₁₁H₁₃N₃O: C, 65.0; H, 6.5; N, 20.7. Found: C, 65.3; H, 6.1; N, 20.9%.

4-Methoxy-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine (7b):

¹H NMR (400 MHz, CDCl₃): δ 8.19 (d, J = 6.0 Hz, 1H), 7.36 (s, 1H), 6.68 (t, J = 5.6 Hz, 1H), 5.98 (s, 1H), 3.90 (s, 3H), 2.61 (s, 3H), 2.29 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 167.4, 155.4, 149.7, 141.8, 141.1, 109.0, 107.9, 100.3, 55.5, 14.6, 13.7. MS-ESI⁺: m/z = 203.1. Anal. Calcd for C₁₁H₁₃N₃O: C, 65.0; H, 6.5; N, 20.7. Found: C, 65.4; H, 6.2; N, 21.1%.

4-(Trifluoromethyl)-2-(1H-pyrazol-1-yl)pyridine (8a):

¹H NMR (400 MHz, CDCl₃): δ 8.64 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.99 (t, J = 7.7 Hz, 1H), 7.78 (s, 1H), 7.56 (d, J = 7.5 Hz, 1H), 6.51 (d, J = 1.3 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 151.7, 148.6 (q, J = 36.2 Hz), 142.9, 140.2, 127.7 (q, J = 285.6 Hz), 117.7 (q, J = 2.2 Hz), 115.4 (q, J = 1.0 Hz), 108.6. MS-ESI⁺: m/z = 213.1. Anal. Calcd for C₉H₆F₃N₃: C, 50.7; H, 2.8; N, 19.7. Found: C, 50.9; H, 2.5; N, 19.9%.

4-(Trifluoromethyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine (8b):

¹H NMR (400 MHz, CDCl₃): δ 8.56 (d, J = 4.4 Hz, 1H), 8.20 (s, 1H), 7.33 (d, J = 7.8 Hz, 1H), 6.03 (s, 1H), 2.68 (s, 3H), 2.32 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 155.6, 150.9, 148.6, 142.3, 141.2 (q, J = 33.6 Hz), 129.0, 124.6 (q, J = 276.4 Hz), 115.8 (q, J = 1.2 Hz), 111.5 (q, J = 1.6 Hz), 15.0, 13.7. MS-ESI⁺: m/z = 241.1. Anal. Calcd for C₁₁H₁₀F₃N₃: C, 54.8; H, 4.2; N, 17.4. Found: C, 55.1; H, 4.0; N, 17.7%.

6-(Trifluoromethyl)-2-(1H-pyrazol-1-yl)pyridine (9a):

¹H NMR (400 MHz, CDCl₃): δ 8.60 (m, 2H), 8.28 (s, 1H), 7.80 (s, 1H), 7.41 (d, J = 4.8 Hz, 1H), 6.52 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 151.5, 146.8 (q, J = 32.2 Hz), 142.8, 140.5, 127.6, 123.0 (q, J = 272.6 Hz), 117.6 (q, J = 2.6 Hz), 115.3 (q, J = 1.4 Hz), 108.4. MS-ESI⁺: m/z = 213.1. Anal. Calcd for C₉H₆F₃N₃: C, 50.7; H, 2.8; N, 19.7. Found: C, 50.9; H, 2.3; N, 20.0%.

6-(Trifluoromethyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine (9b):

¹H NMR (400 MHz, CDCl₃): δ 8.14 (d, J = 8.4 Hz, 1H), 7.93 (t, J = 8.2 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 6.04 (s, 1H), 2.71 (s, 3H), 2.32 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 167.4, 155.4, 153.0, 151.8, 150.5, 149.8, 141.8 (q, J = 30.8 Hz), 122.4 (q, J = 268.2 Hz), 114.0 (q, J = 1.8 Hz), 109.1 (q, J = 1.0 Hz), 100.3, 14.6, 13.7. MS-ESI⁺: m/z = 241.1. Anal. Calcd for C₁₁H₁₀F₃N₃: C, 54.8; H, 4.2; N, 17.4. Found: C, 55.0; H, 3.8; N, 17.8%.

5-Chloro-2-(1H-pyrazol-1-yl)pyridine (10a):

¹H NMR (400 MHz, CDCl₃): δ 8.53 (s, 1H), 8.37 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.80–7.75 (m, 2H), 6.49 (d, J = 1.6 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 149.9, 146.7, 142.5, 138.5, 129.1, 127.2, 113.4, 108.3. MS-ESI⁺: m/z = 179.0. Anal. Calcd for C₈H₆ClN₃: C, 53.5; H, 3.4; N, 23.4. Found: C, 53.7; H, 3.0; N, 23.9%.

5-Chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine (10b):

¹H NMR (400 MHz, CDCl₃): δ 8.36 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 6.01 (s, 1H), 2.63 (s, 3H), 2.30 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 152.0, 151.2, 146.1, 141.8, 138.0, 128.4, 116.5, 109.5, 14.7, 13.7. MS-ESI⁺: m/z = 207.1. Anal. Calcd for C₁₀H₁₀ClN₃: C, 57.8; H, 4.9; N, 20.2. Found: C, 57.6; H, 4.6; N, 20.6%.

2-(3,5-Dimethyl-1H-pyrazol-1-yl)pyrazine (12b):

¹H NMR (400 MHz, CDCl₃): δ 9.26 (s, 1H), 8.39 (d, J = 3.0 Hz, 2H), 6.06 (s, 1H), 2.66 (s, 3H), 2.33 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 151.2, 149.9, 142.5, 141.2, 140.7, 138.4, 110.0, 14.6, 13.8. MS-ESI+: m/z = 174.1. Anal. Calcd for C₉H₁₀N₄: C, 62.1; H, 5.8; N, 32.2. Found: C, 62.5; H, 5.5; N, 32.6%.

Crystal structure determination

Crystallographic data for complex 1 were collected on an Xcalibur Eos Gemini diffractometer with Mo-K_α radiation (λ = 0.71073 Å) at ambient temperature. The data were corrected for Lorentz polarization factors as well as for absorption. The structure was solved by direct methods and refined by full-matrix least-squares methods on F² with the SHELX-97 program. ³⁹ Crystal data, as well as details of data collection and refinements of 1, are summarized in Table 3. The Cambridge Crystallographic Data Centre (CCDC) deposition number is 1583423. These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/datarequest/cif.

Table 3.

Crystallographic data for complex 1.

Empirical formula	C54H46BrCuF6N3O2P3
Fw	1119.30
Crystal system	Monoclinic
Space group	P21/c
a (Å)	17.9246(4)
b (Å)	21.3341(4)
c (Å)	14.7201(3)
α (°)	90
β (°)	113.918(3)
γ (°)	90
Volume (Å3)	5145.7(2)
Goodness-of-fit (GOF)	1.068
F(000)	2280.0
Reflections collected	93,565
Independent reflections	9476
Final R indices [I > 2σ(I)]	R1 = 0.0536, wR2 = 0.1638
R indices (all data)	R1 = 0.0677, wR2 = 0.1725