Pd-N -Heterocyclic carbene catalysed Suzuki-Miyaura coupling reactions in aqueous medium

A new series of methyl substituted imidazole-based N -heterocyclic carbene (NHC) palladium complexes (PdCl 2 (L 1 )NHC(L 1 =pyridine) is reported. Structural definitions of Pd-PEPPSI complexes were determined by NMR spectroscopy, elemental analysis and LC-MS spectroscopy techniques. To evolve a more efficient catalytic system for electronically different aryl chloride substrates on the Suzuki cross-coupling reaction, complexes were used as pre-catalyst. Activity of palladium(II)-NHC complexes screened under mild reaction conditions in aqueous media. With this catalytic system, the reaction proceeded in moderate or good yields with low catalyst loading (0.1 mol%)


Introduction
The development of N-heterocyclic carbenes (NHC) and their different metal complexes has provided a new approach in homogeneous catalysis. 1With these developments, numerous metal-NHC complexes with the inclusion of Ag, 2 Ru, 3 Ir, 4 Rh, 5 and Pd 6 have been prepared.Although there are numerous metal complexes of NHCs, Pd-NHC complexes have particular importance due to their robustness regarding air, moisture and high temperature.The basis of this interest lies in strong σ-donor and weak π-acceptor ability and the ease of adjusting the steric effects of NHC by nitrogen atoms.1][12][13][14] Organ at al. synthesized different types of palladium N-heterocyclic carbene PEPPSI complexes (PEPSSI=Pyridine-Enhanced Pre-catalyst Preparation Stabilization (and) Initiation) in 2006. 157][18] Following these studies, PEPPSI complexes have been extensively studied, and it has been reported that these complexes exhibit very good catalytic and biological activity. 19 The Suzuki coupling reaction is one of the most preferred reactions for C-C bond formation reactions due to the mild reaction conditions.Capretta et al. reported the first NHC-based Suzuki protocol. 27Recently, important advanced studies in the field of well-defined and air-stable palladium-NHC complex-catalyzed Suzuki-Miyaura reactions were published by Glorius, 28 Beller, 29 Herrmann, 30 Nolan, 31 Organ, 32 and others. 11,33- 38However, most of these catalytic systems are need to optimise due to the requirement for hazardous solvents, harsh reaction conditions and high catalyst loading.Catalytic systems that use water as the solvent are inherently safer processes, and offer significant advantages. 39For example, the poor solubility of Suzuki products in water is one of the advantages of this type system because of simplify separation of the desired products from the reaction medium.Considering these important points, to demonstrate the usefulness of electron-rich imidazol based palladium complexes 2a-d, we investigated the catalytic performance of the compounds as co-catalysts in Suzuki-Miyaura coupling reactions in aqueous media.

Result and Discussion
The imidazole-based NHC precursors 1a-d were synthesized according to the literature (Scheme 1) and the spectroscopic data of 1a-d were consistent with the corresponding literature. 40,41Pd-PEPPSI complexes 2a-d were synthesized using Organ's method (Scheme 1), i.e. the reaction of NHCs 1a-d with PdCl 2 in pyridine at 80 o C in the presence of K 2 CO 3 , to provide the NHC palladium complexes 2a-d in 86%, 79%, 85%, 73% respectively.The 13 C{ 1 H} NMR spectra provide information on complex formation, for example an increasing downfield shift of the NCN carbon from 1a-d to 2a-d; i.e. the 13 C{ 1 H} N-C-N shifts of 1a-d and 2a-d were 137.5 and 152.5 ppm, 137.2 and 151.3 ppm, 137.3 and 161.2 ppm, and 137.7 and 151.2 ppm, respectively.
In the first instance, to find the optimum conditions for the Suzuki coupling reaction, an extensive screening of the reaction conditions was carried out using common mineral bases with different solvent variations under standard conditions.To assess the influence of the solvent, we used 4-chloroacetophenone as the substrate and K 2 CO 3 as the base (2a:1 mol%, 4-chloroacetophenone (1 mmol), PhB(OH) 2 (1.5 mmol), 80 o C, 3h).In all cases, the reactions were heated for 3h at 80 o C.After several reactions, the results showed that this catalytic system is effective with all solvents and bases, but the best one is K 2 CO 3 -DMF/H 2 O.The optimum yield was obtained with the most polar solvents in an equal ratio of DMF/H 2 O.The results are summarized in Table 1, entries 1-12.These optimum results were attributed to water due to its high polarity and the good solubility of the base in water.Solubility of the base is important to generate water-soluble aryl boronate derivatives. 42The use of pure DMF, H 2 O, i-PrOH or 1,4-dioxane afforded lower yields than the use of a mixture of DMF and water in equal proportions.4][45] Therefore, it is hard to make a comparison of palladium catalysts, but we can make a provisional comparison with the Organ system ((Pd-PEPPSI: 2 mol %, chloroanisole (1 mmol), PhBF 3 K (1.0 mmol), 60 o C, 24h, MeOH) in the Suzuki-Miyaura reaction. 15 series of activated and non-activated aryl chloride substrates with phenylboronic acid was used under the optimized conditions described above (Table 2).The results show that complexes 2a-d were sufficiently active catalysts in the Suzuki coupling reaction, similar to Organ's catalyst under similar reaction conditions.When catalytic activity of 2a-d was compared in the Suzuki coupling reaction, complex 2a gave the best results, in almost each case with different substrates except in the case of chlorobenzene.We attributed these performance differences to the electron richness of 2a.It is known that electron rich Pd-complexes undergo oxidative additions more readily.Also, the steric effect of the catalyst facilitates the reductive elimination of the product from the active catalyst.The general opinion on this issue is that, the steric and electronic properties need to be equipoise to create a highly active catalyst system. 28,43,46,47 e efficiency of our catalytic system is better than the literature [48][49][50] within the meaning of the catalyst loading and aryl chloride substrates.

Conclusions
Herein, we reported synthesize and define highly active, easy to produce and environmentally friendly new Pd-PEPPSI complexes.Due to the structure of the Pd-PEPPSI complexes, the carbene remains electron-rich upon coordination to palladium, which makes the palladium-carbon bond strong and stable.This outstanding property of Pd-PEPPSI complexes creates advantages over other complexes in catalytic cross-coupling reactions.The catalytic activity of 2a-d was moderate and encouraged us to synthesize additional Pd complexes that are electronically and structurally different previously reported Pd-PEPPSI complexes.

Experimental Section
General.Unless stated otherwise, all procedures were carried out under a normal air atmosphere.Chemicals and solvents were purchased from Sigma Aldrich Co. (Dorset, UK) and used without any purification. 1H NMR and 13 C NMR spectra were recorded using a Bruker Avance 400 operating at 400 MHz ( 1 H), 100 MHz ( 13 C) in CDCl 3 .Coupling constants (J values) are given in Hertz.NMR multiplicities are abbreviated as follows: s= singlet, d= doublet, t= triplet, m= multiplet, bs= broad singlet.Melting points were detected by Stuart automatic melting point apparatus (SMP-40).

Preparation of the NHC-palladium-pyridine (PEPPSI) complexes 2a-d
In air, a pressure tube was charged with PdCl 2 (180 mg, 1 mmol), 1a-d (1.1 mmol), K 2 CO 3 (700 mg, 5 mmol) and 3 mL of pyridine.The reaction mixture was heated with vigorous stirring for 17 h at 80 o C then cooled to room temperature and diluted with dichloromethane (DCM).A short silica column was used for purification.All volatiles were evaporated.The yellow solid residue was washed with hexane (2x10 mL) and diethyl ether (2x10 mL).The crystalline yellow solid was used in the Suzuki reaction as obtained.

General procedure for Suzuki Cross-Coupling reaction
In air, 2a-d (0.1 mol%, aryl chloride (1.0 mmol), phenylboronic acid (1.5 mmol), K 2 CO 3 (2 mmol) and 3 mL of a mixture of water and DMF (1:1) were added to a small round-bottom flask and the mixture was heated at 80 o C for an appropriate period of time.The reaction mixture was cooled to room temperature and 10 mL of water was added to the reaction mixture and extracted with Et 2 O.The organic phase was dried with MgSO 4 and filtrated by short chromatography on silica gel column.Then volatiles were removed under reduced pressure and yield distribution was determined by GC using undecane as internal standard.The yields are based on corresponding aryl chlorides.All catalytic reactions were duplicated.All coupling products obtained via Suzuki-Miyaura coupling reaction are previously reported compounds, and were identified by comparison of our data with that available in the literature.

Table 1 .
The effect of solvent and base on yield in the Suzuki coupling reaction a

Table 1 .
ContinuedThis catalytic system led to the investigation of cheap and abundant sodium and potassium carbonate bases that have poor solubility, except in water.All carbonate bases resulted in sufficient conversions, but potassium carbonate demonstrated significantly better performance (Table1, entry 9, 10).

Table 2 .
The Suzuki coupling reaction of aryl chlorides a © ARKAT USA, Inc