Pd-SILP-Fe 3 O 4 @SiO 2 : An efficient supported ionic liquid phase catalyst for the Mizoroki-Heck coupling

An efficient method for the Mizoroki-Heck coupling of aryl halides with alkenes employing already reported palladium tagged, magnetic nanoparticle supported, ionic liquid phase catalyst (Pd-SILP-Fe 3 O 4 @SiO 2 ) in water under aerobic conditions has been developed. Various di-substituted alkenes were synthesized with excellent yields using a highly water dispersible Pd-SILP-Fe 3 O 4 @SiO 2 catalyst. This nanocatalyst displayed high thermal stability, compatibility in aqueous systems, high catalytic efficiency, high turnover frequencies (TOF), easy magnetic recovery, and reusability up to 6 th run. The main advantages of the protocol are its robustness, mild reaction conditions, easy set-up, easy workup, low Pd loading (0.001 mol% of Pd), higher yields, and use of water as a green solvent, which makes it both environmentally and economically appealing.


Introduction
The construction of a carbon-carbon (C-C) bond via cross-coupling reactions is one of the most important and powerful tools in synthetic organic chemistry; as a result, various new coupling reactions forming the C-C bond were invented and developed by the scientific community since 1855.These coupling reactions played an enormously decisive role in shaping synthetic organic chemistry, conceptualizing and building an innovative and highly significant process 1 .These reactions stimulated keen interest and dedicated efforts towards broadening the scope of these reactions which led to the development of milder conditions with lower Pd loadings, use of more efficient catalytic systems involves a variety of ligands having different electronic and steric properties.Ultimately, the employment of these potent ligands resulted in the discovery of novel cross-couplings that produced additional bonds (e.g.C-N, C-O, C-P, C-S, C-B).
These coupling reactions played an important role in the synthesis of a variety of pharmaceutical drugs and their precursors, fine chemicals, functionalized structures, biologically active compounds, natural products, organic building blocks and their intermediates, etc 2,3 .The Nobel Prize in Chemistry-2010 was awarded jointly to Richard F. Heck, Eiichi Negishi and Akira Suzuki for "palladium-catalyzed cross couplings in organic synthesis" 1 .The Mizoroki-Heck crosscoupling is one of the powerful and simple method for the coupling of alkenes with a variety of aryl or alkyl halides to afford substituted alkenes, dienes and conjugated polymers, etc 4,5 .Mizoroki and co-workers reported a palladiumcatalyzed arylation of olefinic compounds with aryl iodides using palladium black obtained from palladium chloride as a catalyst and potassium acetate as a base in methanol at 120 °C6 (Figure 1).

Figure 1 Palladium-catalyzed arylation of olefinic compounds reported by Mizoroki
Later on, Heck and co-workers independently reported a coupling reaction under much more convenient laboratory conditions between halides (aryl, benzyl, styryl) with terminal alkenes (styrene, 4-nitrostyrene, cis-1-phenyl-1propene, methyl acrylate) using palladium acetate as catalyst and tri-n-butylamine as a base without the use of solvent at steam temperature 7 (Figure 2).

Figure 2 A coupling reaction reported by Heck
The Mizoroki-Heck coupling is broadly defined as "the palladium-catalyzed coupling of alkenyl or aryl (sp 2 ) halides or triflates with alkenes to yield highly substituted vinyl arenes" (Figure 3).Nowadays, the Mizoroki-Heck reaction stands as a highly robust, reliable and efficient way to generate carbon-carbon bonds, especially in creating tertiary and quaternary stereo centers and intramolecular ring formation.This reaction was highly explored in various areas because of its high efficiency, high chemo-selectivity, simple reaction conditions, and use of cost-effective and low toxic reagents 8 .

Figure 3 General reaction of Mizoroki-Heck coupling
The Mizoroki-Heck coupling can be executed using heterogeneous or homogeneous Pd (0) or Pd (II) complexes with a variety of ligands.Generally, in homogeneous catalysis, phosphines are the most commonly used ligands 9 .It is observed that a homogeneous catalyst such as a complex of palladium (0) or palladium (II) display admirable performance in the Heck coupling 10 .However, homogeneous catalysis has some significant downsides, including the high toxicity of the catalyst and ligands, their susceptibility to air and moisture and their expensive cost, which limits their large-scale use 10 .Consequently, over the past few decades, significant efforts have been made to develop phosphine-free Pd complexes that catalyze the Heck coupling using other stable ligands, such as N-heterocyclic carbenes 11 , bispyridine 12 , bispyrazole derivatives 13 , bisimidazole 14 , oximes 15 and Schiff bases 16 .Despite the impressive advancements made in Mizoroki-Heck coupling, there is still a significant need for cost-effective, environmentally friendly and practical cross-coupling methods that use heterogeneous catalysts with extremely low catalyst loadings and have high turn-over numbers.Researchers have immobilized the parent homogeneous Pd-catalysts on various types of organic or inorganic supports to create heterogeneous catalysts, which would provide the benefits such as easy separation and recycling [17][18][19] .
A new class of ILs called supported ionic liquids (SILs) is designed by immobilizing ILs onto a porous high area support material surface either by covalent bonding or adsorption interactions, which possess advantages of ionic liquid media with solid support materials 20 .The most common supports used to immobilize ILs are silica, polymer, cellulose, graphene oxide, iron oxides/ferrite/magnetic nanoparticles (Fe3O4/MNP), activated carbon, carbon nanotubes, chitosan, modified montmorillonite and molecular sieves [21][22] .This SILP catalysts are highly efficient for the Mizoroki-Heck coupling.
In this context, highly water dispersible palladium tagged ferrite nanoparticle supported ionic liquid phase catalyst Pd-SILP-Fe3O4@SiO2 (Figure 4) which was previously synthesized by our group 23 was employed for the Mizoroki-Heck coupling.

General
Melting points were determined in an open capillary and are uncorrected.Infrared spectra were measured with a Bruker ATR infrared spectrophotometer. 1 H and 13 C NMR spectra were recorded on a Bruker AV 400 (400 MHz for 1 H and 100 MHz for 13 C NMR) spectrometer using CDCl3 and DMSO-d6 as solvent and tetramethylsilane (TMS) as an internal standard.

General procedure for Mizoroki-Heck coupling
A mixture of aryl halide (1.0 mmol), alkene (1.1 mmol), triethylamine (2.0 mmol), and catalyst Pd-SILP-Fe3O4@SiO2 (50 mg) in water (5 mL) was stirred at 90 °C for an appropriate time under aerobic condition.The progress of a reaction was monitored by thin-layer chromatography (TLC) using alumina-backed silica gel 60 (F254) plates eluting with an ethyl acetate-petroleum ether solvent system.After completion of the reaction, the mixture was cooled to room temperature; the catalyst was separated magnetically using a bar magnet.The product was extracted with ethyl acetate (4 × 5 mL) and the combined organic layer was washed with brine solution (5 mL) and dried over MgSO4.The organic layer was then concentrated on a rotary evaporator afforded corresponding crude product.The crude product obtained was purified by column chromatography using ethyl acetate-petroleum ether (1-20%) as eluent to afford a pure coupling product

Reusability of the catalyst
After completing the model reaction, the catalyst was magnetically recovered using a bar magnet and washed with ethanol (2 x 5 mL) and acetone (2 x 5 mL).The recovered catalyst was dried under reduced pressure and reused for the next cycle employing similar reaction conditions.The reusability of the catalyst was investigated for up to 6 cycles for Mizoroki-Heck coupling under optimized reaction conditions.

Result and discussion
The excellent performance of Pd-SILP-Fe3O4@SiO2 for the Sonogashira coupling inspired us to explore its catalytic efficiency for other coupling reactions.To accomplish this goal, a highly water dispersible palladium tagged ferrite nanoparticle supported ionic liquid phase catalyst (Pd-SILP-Fe3O4@SiO2) was employed for the Mizoroki-Heck coupling.
Figure 4 Pd-SILP-Fe3O4@SiO2 catalyst An efficient Pd-SILP catalyst in hand, initially, we focused on optimization of parameters such as suitable solvent, base and amount of catalyst for the Mizoroki-Heck coupling.The model reaction has been carried out using iodobenzene and styrene as coupling partners and dimethylformamide as a solvent at room temperature in the presence of triethylamine as a base and Pd-SILP-Fe3O4@SiO2 as a catalyst.No product formation was observed even after 12 hours (Entry 1, Table 1); hence reaction was carried out under reflux conditions.Gratifyingly, an excellent yield of 92% within 2 h was observed.(Entry 2, Table 1) Inspired by these results, we shifted our attention towards optimizing the best suitable solvent for the reaction.A model reaction has been carried out using various solvents, keeping other conditions same.It was observed that water-mediated reactions afforded a higher yield of 95% with a shorter reaction time of 2 h.(Entry 4, Table 1) Hence water was selected as the best suitable solvent for the Mizoroki-Heck coupling reaction using Pd-SILP-Fe3O4@SiO2 as a catalyst under reflux conditions.Reaction conditions: Iodobenzene (1 mmol), styrene (1.1 mmol), Pd-SILP-Fe3O4@SiO2, Et3N (2 mmol), water (5 mL), reflux, a Isolated yield.
Optimization of the catalyst loading was done by employing the different amounts of catalyst for the model reaction.It was observed that only 50 mg of catalyst was sufficient to carry out the reaction efficiently (Entry 3, Table 3).Notably, there was no difference in yield and reaction time when catalyst loading was increased.However, a longer time was required to complete a reaction with an inferior yield when reduced catalyst loading.Further, no product formation was observed when the reaction was executed without the catalyst, which indicates the role of Pd-SILP-Fe3O4@SiO2 as catalyst.
Finally, model reaction has been carried out at various temperatures to investigated the optimum temperature.It was observed that 90 °C is the optimum temperature for the model reaction above which yield remains constant while below it yield decreases sharply.(Entry 4, Table 4) Reaction conditions: Iodobenzene (1 mmol), styrene (1.1 mmol), Pd-SILP-Fe3O4@SiO2 (0.05 g), Et3N (2 mmol), water (5 mL), a Isolated yield.
With optimized reaction conditions in hands, the generality of the method was tested by performing Mizoroki-Heck coupling between diversely substituted aryl halides and a variety of alkenes.A reaction of styrene with aryl iodide afforded a higher yield of 95% with a high turn-over frequency of 47500 h -1 (Entry 1, Table 5), whereas aryl chloride displayed a lower yield of 71% with a lower turn-over frequency (14200 h -1 ) (Entry 5, Table 5).Aryl halides with electron-withdrawing groups afford higher yields (Entries 3-5, 8-9, 12, 15, Table No. 5) than those with electrondonating groups (Entries 2, 11, 13-14, Table 5).Next, to explore the generality of the protocol, a variety of alkenes such as methyl acrylate, tert-butyl acrylate and acrylonitrile were employed for the coupling reactions.It was observed that all the coupling reactions with aryl iodides work smoothly with the excellent yield of the product, while aryl bromides and chlorides afforded a moderate yield.Synthesized compounds were characterized by various spectroscopic methods.The IR spectrum of methyl (E)-3-(4-acetylphenyl)acrylate (Entry 7, Table 5) depicted significant carbonyl stretching frequency band at 1721 and 1707 cm -1 due to α-β unsaturated ester and ketone group, respectively.Absorption bands appeared around 1674, 1421 cm -1 suggesting the presence of C=C in the compound.Further, band at 1620 cm -1 is due to the presence of trans double bond, whereas C-H wag of trans double bond is observed at 956 cm -1 . 1 H NMR spectrum of the same compound displayed two singlets at δ 2.62 and 3.83 ppm for methyl protons of acetyl group and methoxy proton of acrylate, respectively.Two trans olefinic protons appeared as a doublet at δ 6.53 and 7.71 ppm with a coupling constant, J = 16 Hz.Further, two doublets at δ 7.61 and 7.97 ppm correspond to four aromatic protons with coupling constant, J = 8 Hz. 13  The catalytic efficiency of the synthesized catalyst Pd-SILP-Fe3O4@SiO2 was compared with numerous recoverable, heterogeneous and Pd-SILP catalysts reported previously for the Mizoroki-Heck coupling of iodobenzene and styrene.
From these results, it was observed that the catalyst, Pd-SILP-Fe3O4@SiO2 was superior in terms of yield, metal loading, reaction time and turn-over number to most of the heterogeneous and Pd-SILP catalytic systems reported in the literature.Further, most of the literature reported high temperature (above 100 o C) for the Mizoroki-Heck coupling, whereas Pd-SILP-Fe3O4@SiO2 is utilized at 90 °C (Entry 10, Table 6).Finally, the reusability of the catalyst, Pd-SILP-Fe3O4@SiO2 was investigated for the reaction between iodobenzene and styrene under optimized reaction conditions.The formed product was extracted from the reaction mixture using ethyl acetate and the catalyst, Pd-SILP-Fe3O4@SiO2, was separated with the help of a bar magnet.The recovered catalyst was reused for at least 6 cycles without significant loss in the catalytic activity (Fig. 5).

Conclusion
We have explored Pd-SILP-Fe3O4@SiO2 as a highly water dispersible, magnetically separable and robust heterogeneous catalyst for the synthesis of aryl alkenes through Mizoroki-Heck coupling of a variety of olefins and aryl halides.The Mizoroki-Heck coupling of aryl iodides, bromides and even less reactive chlorides with olefins produced corresponding coupling products in good to excellent yield.The reaction was carried out using water as a green solvent with very low loading (0.001 mol%) of the catalyst.Easy recovery and reusability of catalyst for at least 6 consecutive reaction cycles without significant loss in the catalytic activity makes the protocol highly efficient, economical and ecological.

Table 3
Optimization of catalyst loading for Mizoroki-Heck coupling

Table 4
Temperature optimization for the Mizoroki-Heck coupling

Table 5
Mizoroki-Heck coupling of a different aryl halide with alkenes

Table 5 )
13e IR spectrum of the (E)-1-(4-styrylphenyl)ethan-1-one show carbonyl stretching frequency band at 1691 cm -1 .The absorption bands at 1588, 1407 cm -1 are due to the C=C stretching frequency.Further, a band observed at 1616 cm -1 is due to the presence of trans double bond, whereas C-H wag of trans double bond observed at 958 cm -1 . 1 H NMR spectrum of the same compound exhibited a singlet at δ 2.61 for methyl protons of the acetyl group.Two trans olefinic protons appeared as a two doublets at δ 7.13 and 7.23 ppm with a coupling constant J = 15.9Hz.Two aromatic protons appeared as doublet between 7.95 ppm with coupling constant J = 8 Hz.Remaining eight aromatic protons appeared as three sets of multiplet between 7.28 -7.32, 7.35-7.40and7.53-7.60ppmforfour protons, respectively.13CNMR spectrum of the same compound displayed two remarkable signals at δ 26.58 and 197.49ppm for methyl carbon and carbonyl carbon, respectively.A signal for the olefinic carbons was observed at δ 128.89 and 131.51 ppm, whereas signals appeared at δ 126.52, 126.84, 127.49, 128.35, 128.81, 136.01, 136.74, and 142.05 ppm represented aromatic carbons in the product.IR and NMR data are in agreement with the expected structure. Nxt, we switched over to the electron-withdrawing olefin, methyl acrylate and carried out its coupling with 4-iodoacetophenone under optimized reaction conditions.
C NMR spectrum of the same compound demonstrated signals at δ 26.68 and 51.90 ppm for methyl carbons.A significant signal observed at δ 197.29 and 166.94 ppm is due to the carbonyl carbon of the ketone and ester groups, respectively.A signals for the olefinic carbons were observed at δ 143.32, and 120.38 ppm, whereas signals for aromatic carbons w er e observed at δ 128.16, 128.88, 138.09, 138.74 ppm.All the spectroscopic data is in agreement with the expected structure.