A highly active and recyclable homogeneous NHC–palladium catalyst with pH- and light-sensitive tags for the Suzuki–Miyaura coupling reactions of aryl halides with arylboronic acids

Abstract

The design and synthesis of a stable, highly active, and recyclable homogeneous palladium catalyst for Suzuki–Miyaura coupling reactions is of great interest. A well-defined N-heterocyclic carbene (NHC) Pd(II) complex with pH- and light-sensitive nitrobenzospiropyran (SP) tags has been synthesized in good yields via a series of simple steps. This complex is a homogeneous catalyst which has excellent reactivities for the Suzuki–Miyaura coupling of aryl bromides and aryl chlorides with arylboronic acids. Significantly, at a low loading (0.2 mol%), this catalyst has very good recyclability in an i-PrOH–H₂O solvent system (1 : 1 v/v), under mild conditions. By making use of the pH- and light-sensitive SP tags, the catalyst can be recovered and reused seven times.

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Both homogeneous and heterogeneous catalysis play essential roles in organic chemistry. Heterogeneous catalysts are usually more stable and are easier to separate from the reaction products,^1,2 whereas, homogeneous catalysts are more active and have better selectivities. The main disadvantage of homogenous catalysts is that they are difficult to isolate and reuse.^3,4 From economic and ecological standpoints, catalyst recovery and reuse is imperative and the separation and recycling of homogeneous catalysts is currently a main objective in the area of green chemistry.⁵

The palladium-catalyzed Suzuki–Miyaura coupling reaction of aryl halides with arylboronic acids is one of the most powerful tools to construct C–C bonds and is widely used to make biaryl derivatives which are important intermediates in the syntheses of natural products, pharmaceuticals, and other materials.^6,7 Suzuki–Miyaura coupling reactions generally proceed well in homogeneous Pd/ligand catalytic systems. Phosphine ligands are commonly employed in Pd/ligand catalytic systems in order to promote the efficiencies of coupling reactions.^8–11 However, most phosphine ligands are costly, sensitive to air, and degrade at high temperature. Additionally, it is difficult to remove the decomposed phosphine ligands from the reaction products. These issues limit the application of phosphine ligands to industrial processes.

Bulky N-heterocyclic carbenes (NHCs) are often used as σ-donor ligands in metal coordination chemistry. They have excellent stability and high dissociation energies.¹² Due to their steric and electronic properties, NHCs can effectively enhance the catalytic activity and stability of palladium catalysts.^13,14 Over the past few years, the use of NHCs as supporting ligands in palladium catalysts has become increasingly popular.¹⁵ NHC–Pd(II) complexes with a 1 : 1 ratio of NHC ligand to Pd, especially those having one dominant NHC ligand, two anionic ligands, and/or other neutral ligands have been found to be very active.^16–18 However, these homogeneous catalysts cannot be reused well. In this work, an effective and recyclable NHC ligand/Pd catalyst with a 1 : 1 ratio has been developed for the Suzuki–Miyaura coupling of aryl halides with arylboronic acids.

In previous studies, we reported a highly efficient and recyclable homogeneous Ru olefin metathesis catalyst containing nitrobenzospiropyran (SP).¹⁹ These SP tags have photochromic properties and this property was used to separate this homogeneous catalyst from the reaction products. Using this same method, Zhang et al. were able to recover a NHC–copper(I) complex.²⁰ Spiropyrans are not only light-sensitive but also pH-sensitive and so in this work, both the pH- and light-sensitive properties of a SP-tagged NHC–Pd(II) complex were investigated in order to develop a method to recover homogeneous catalysts.

Scheme 1 illustrates the synthetic route for the SP tagged NHC–Pd(II) complex 6. The SP tagged ligand 5 was synthesized in moderate to good yields using 4-bromo-2,6-dimethyl-phenylamine as the starting material. The 4-bromo-2,6-dimethyl-phenylamine was treated with glyoxal at room temperature to give N,N′-bis(4-bromo-2,6-dimethylphenyl)imine, which was subsequently refluxed with sodium borohydride to generate 1. Refluxing of 1 with ethyl acrylate in toluene in the presence of Pd(PPh₃)₄ and triethylamine (TEA) gave 2, which when heated with NaOH(aq) generated 3. When 3 was stirred with SP, dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) in CH₂Cl₂ in the dark at 30 °C, 4 was formed. Next, 5 was prepared by reacting commercially available 2,3,4,5,6-pentafluorobenzaldehyde with 4 in the presence of acetic acid.²¹ The target complex 6 was formed as a royal purple solid after refluxing 5 with (Pd(allyl)Cl)₂.

Scheme 1 Synthesis of SP-tagged NHC–palladium complex 6. Reagents and conditions: (i) glyoxal, MeOH, stirred; (ii) NaBH₄, reflux; (iii) ethyl acrylate, Pd(PPh₃)₄, toluene, reflux; (iv) NaOH (aq), MeOH, reflux; (v) SP, DCC, DMAP; (vi) 2,3,4,5,6-pentafluorobenzaldehyde, acetic acid, CH₂Cl₂; (vii) (Pd(allyl)Cl)₂, toluene, 80 °C, stirred.

In order to determine if the SP-functionalized NHC–Pd(II) complex 6, has both pH- and light-switching properties, UV-adsorption experiments were performed. Fig. 1 shows the three states in which this system exists as a function of light and pH. The UV-vis spectrum of 6 in i-PrOH–H₂O (1 : 1 v/v) has no absorption bands from 400–800 nm (black line). However, when the pH of the solution was adjusted to 12 with KOH and the complex was irradiated with 365 nm light, a band with λ_max at 420 nm appeared (red line). According to Boyd et al. this indicates that complex 8a (or 8b) was formed.²² At the same time, the complex 8 was also characterized by ¹H NMR and the results showed that it's a mixture of 8a and 8b (see ESI†). When the pH of the solution was adjusted to neutral, the λ_max of the absorption band shifted to 520 nm (blue line) which indicates that complex 7 was formed.²² When complex 7 was irradiated with light (λ > 380 nm) for two minutes, it was converted back into complex 6 as indicated by the disappearance of the absorption band at 520 nm (green line).²³

Fig. 1 Structures and Vis-UV spectra of complex 6 as a function of pH and light in i-PrOH–H₂O (1 : 1 v/v). Black line – irradiation of 6 produces no significant absorbance from 450–650 nm regions. Red line – addition of KOH caused the formation of 8 with an absorbance band at 420 nm. Blue line – neutralization with HCl generated 7 with an absorbance band at 520 nm. Green line – irradiation of complex 7 with light (λ > 380 nm) for two minutes caused complex 7 to convert back into complex 6.

Next, the catalytic activity of 6 for the Suzuki–Miyaura reaction of 4-bromotoluene with phenylboronic acid was investigated. In order to optimize the reaction conditions, KOH and K₂CO₃ in combination with different solvents were investigated using 4-bromotoluene (0.25 mmol), phenylboronic acid (0.25 mmol) and catalyst 6 (0.1 mol%) as a model reaction system. The effect of the solvent was investigated first. The best result (99% yield) was obtained in i-PrOH–H₂O (1 : 1 v/v) in the present of KOH after reacting for 3.5 h at 30 °C. Methanol and methanol/water (1 : 1 v/v) both gave moderate yields (67% and 55% respectively). When other solvents (DMF/H₂O (1 : 1 v/v), THF/H₂O (1 : 1 v/v), i-PrOH, DMF, THF, toluene, or H₂O) were employed, no products were obtained. The base also had a pronounced effect on the Suzuki–Miyaura reaction of the deactivated aryl bromide and KOH was the most effective with a yield of 99%. The use of K₂CO₃ resulted in a lower yield (48%) due to its weak basicity. The results for the different solvents and bases are presented in Table S1 (see ESI†).

Using these optimized conditions, the activity of 6 for Suzuki–Miyaura reactions of various aryl halides with phenylboronic acid was then tested. The results are shown in Table 1. The Suzuki–Miyaura reactions of deactivated aryl halides including 4-iodotoluene, 4-bromotoluene, chlorobenzene, 4-chlorotoluene, p-chlorofluorobenzene and a hindered 2-methylbromobenzene all proceeded with high yields (99%, 99%, 92%, 78%, 90% and 94%, respectively) (entries 1–6). However, the reactions of 4-nitrobromobenzene, 4-bromobenzaldehyde and 2-bromopyridine had lower yields of 20%, 42% and 30%, respectively (entries 7–9) due to their poor solubilities in i-PrOH–H₂O (1 : 1 v/v). The catalyst system is homogeneous and a clear picture about it is shown in Fig. S1 (see ESI†).

Table 1 Suzuki–Miyaura reaction of aryl halides with phenylboronic acid^a

Entry	X–R	Product	Yield^b (%)	Entry	X–R	Product	Yield^b (%)
a Reactions were carried out using 10a (0.25 mmol, 1 equiv.), 9 (0.25 mmol, 1 equiv.), KOH (0.5 mmol, 2 equiv.), H2O (0.5 mL) and i-PrOH (0.5 mL) at 30 °C, for 3.5 h.b Isolated yields.c 1.25 h.
1		11a	99^c	6		11d	94
2		11a	99	7		11e	42
3		11b	92	8		11f	30
4		11a	78	9		11g	20
5		11c	90

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Next, a variety of electron-rich and electron-poor arylboronic acids were tested under the optimized reaction conditions and the results are shown in Table 2. In most cases, the corresponding biaryls were achieved in high to excellent yields. However, furan-3-boronic acid, a heteroaryl boronic acid, gave unsatisfactory results (entry 8).

Table 2 Suzuki–Miyaura reaction of 4-bromotoluene with boronic acids derivatives^a

Entry	R–B(OH)2	Product	Yield^b (%)	Entry	R–B(OH)2	Product	Yield^b (%)
a Reactions were carried out using 10 (0.25 mmol, 1 equiv.), 9a (0.25 mmol, 1 equiv.), KOH (0.5 mmol, 2 equiv.), H2O (0.5 mL) and i-PrOH (0.5 mL) at 30 °C, for 3.5 h.b Isolated yields.
1		12a	98	5		12e	58
2		12b	95	6		12f	80
3		12c	95	7		12g	63
4		12d	93	8		12h	20

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A plausible mechanism for the formation of 11 (or 12) is illustrated in Scheme 2. First, an active [(NHC)Pd(0)] specie A was generated through a nucleophilic attack of OH⁻ on the allyl moiety followed by reductive elimination.²⁴ The second step involve the generation of intermediate species B in the presence of the aryl halide.²⁵ Then, intermediate C was formed in the presence of phenylboronic acid. Lastly, the coupling product was formed followed by a reductive elimination reaction.

Scheme 2 Proposed activation pathways for Suzuki–Miyaura coupling reactions of aryl halides with arylboronic acids.

Finally, the pH- and light-sensitive properties of the SP-tagged NHC–Pd(II) complex 6 were utilized in order to recover and reuse the catalyst. After 4-bromotoluene was reacted with phenylboronic acid under the optimal reaction conditions, complex 6 was easily recovered from the products by using the simple recovery process shown in Fig. 2. After the reaction, cyclohexane was added to the i-PrOH–H₂O (1 : 1 v/v) product mixture resulting in the formation of two layers. The products dissolved in the upper layer (the cyclohexane and i-PrOH) and complex 8 stayed in the lower layer (the water). The product-layer was then removed. Next, the lower layer was neutralized with HCl and then CH₂Cl₂ was added, again resulting in the formation of two layers. Complex 7 dissolved in the CH₂Cl₂ layer. The catalyst-containing CH₂Cl₂ layer was then irradiated with UV to transform the trans-MC tag into the SP tag. Finally the solvent was removed under vacuum and the recycled catalyst, complex 6, was obtained. Complex 6 was then directly used for another reaction cycle. As shown in Table 3, with a low loading (0.2 mol%), the recovered catalyst exhibited high catalytic activity. Although a small amount of deposits of Pd black accompanied this reaction which resulted in a prolonging in reaction time, the recovered catalyst still retained activity for seven successive cycles. A high turnover number (total TON = 3705) was obtained.

Fig. 2 Schematic for the separation of catalyst 6 from the products.

Table 3 Recycling of 6 for the Suzuki–Miyaura reaction of 4-bromotoluene with PhB(OH)₂^a

Cycle^b (% yield)
	1	2	3	4	5	6	7	8	TON^i
a Reactions were carried out using 4-bromotoluene (0.25 mmol, 1 equiv.), PhB(OH)2 (0.25 mmol, 1 equiv.), KOH (0.5 mmol, 2 equiv.), H2O (0.5 mL) and i-PrOH (0.5 mL) at 30 °C.b Isolated yields.c Reaction time: 1.5 h.d Reaction time: 2.5 h.e Reaction time: 3.0 h.f Reaction time: 12 h.g Reaction time: 1.5.h By ICP-AES analysis based on Pd%.i Total TON.
	98^c	98^c	98^c	98^c	98^d (62^g)	98^e (55^g)	97^f (30^g)	56^f (15^g)	3705
Recovered^h catalyst (mol%)	0.194	0.186	0.177	0.164	0.156	0.145	0.130

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In conclusion, a highly efficient and recyclable homogeneous catalystic system for Suzuki–Miyaura coupling reactions of aryl halides with arylboronic acids has been developed. The catalyst is a NHC–palladium(II) complex with pH- and light-sensitive SP tags. The catalyst is stable and has high catalytic activities under mild reaction conditions. By using the pH and light-sensitive properties of the SP tags, the homogeneous catalyst at a low loading (0.2 mol%) can be recovered and reused seven times. This new method of recycling and recovering a homogeneous catalyst could be an important tool for developing highly active recyclable homogeneous palladium catalysts for C–C coupling or other palladium-catalyzed reactions.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant No. 21102102, 21572158 and 21572155).

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Footnote

† Electronic supplementary information (ESI) available: Full experimental details and characterization data (¹H-NMR, ¹³C-NMR, ¹⁹F-NMR, HRMS and elemental analysis). See DOI: 10.1039/c6ra08272f

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