**"Green" Pericyclic Reactions Assisted by Ionic Liquids**

Rafael Martínez-Palou, Octavio Olivares-Xometl, Natalya V. Likhanova and Irina Lijanova

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/59179

#### **1. Introduction**

Ionic liquids (ILs) are compounds that consist exclusively of ions. These compounds, which can be considered as salts, feature low melting temperatures (generally below 100°C), at which other salts are solids. The cations in these compounds are of organic type and some of the most common structures are heterocyclic such as imidazolium (**1**), pyridinium (**2**), pyrazolium (**3**) and pyperidinium (**4**), or may also be formed by non-cyclic, heteroatom-containing cations such as ammonium (**5**) and phosphonium (6) (Figure 1) [1].

**Figure 1.** Typical cations in ILs.

Where R, R´, R´´, R´´´ are generally alkyl or alkyl functionalized chains.

As for the anions, they can be either inorganic (Cl- , Brand I- , which are known to have been part of the first generation ILs, and others such as [BF4] - , [PF6] - , [SbF6] - , [AlCl4] - , [AuCl4] - , [NO3] - , [NO2] - , [SO4] - ) or in other cases the anion is organic ([AcO]- , Tf- , [N(OTf)2] - , [CF3CO2] - , [CF3SO3] - , [PhCOO]- , [C(CN)2] - , [RSO4] - [OTs]- , and [SCN]- ).

Nowadays, ILs are gaining wide recognition as potential environmental solvents due to their unique properties [2]. Physicochemical properties such as low vapor pressure (evaporation losses are minimized), thermal and chemical stability, catalytic activity, non-flammability and

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non-corrosive properties, which decrease the risk of worker exposure and solvent loss to the atmosphere, make ILs powerful candidates to replace the so-called "volatile organic com‐ pounds" (VOCs) in the development of more environmentally friendly technologies and specially for the petroleum industry [3, 4].

Pericyclic reactions belong to a very important group of organic reactions, including some of the most powerful synthetically useful reactions like the Diels-Alder reaction, 1,3-dipolar cycloadditions, the Alder-ene reaction, Cope and Claisen rearrangements, the 2,3-Wittig rearrangement, diimide reduction, sulfoxide elimination, Fisher indole synthesis and many others.

In the last years, ILs have been employed as reaction media and/or catalysts and co-catalysts to facilitate the curse of many pericyclic reactions. Due to the nature and properties of this kind of compounds, the application of ILs in these reactions has contributed to the development of more efficient and environmentally friendly methodologies. In this chapter, the principles of pericyclic reactions are presented and an overview of the applications of ILs in assisted pericyclic reactions is discussed.

#### **2. Pericyclic reactions**

The term Pericyclic reactions refers to a set of reactions that are characterized by concert‐ ed processes that proceed via cyclic transition states, which can be interpreted according to the Molecular Orbital Theory. Pericyclic reactions are reactions, where a cyclic, conjugat‐ ed system of electrons is created in the transition state, having highly predictable stereo‐ chemical features [5].

The stereochemistry of the pericyclic reactions can be predicted based on the principle of conservation of orbital symmetry, employing the rules proposed by Robert Burns Woodward and Ronald Hoffmann in 1965 (Woodward-Hoffmann rules) [6]. This principle applies only to the concerted pericyclic reactions, and in this case, it serves as a powerful predictive tool.

The Woodward-Hoffmann rules were established by the authors as:


It is said that the organic reactions that obey these rules are allowed by symmetry. Reactions that take the opposite course are forbidden by symmetry and require much more energy if they happen to take place.

The pericyclic reactions are classified according to the number of electrons that are directly involved in the transition state. Processes with 2- and 6-electron (Huckel, 4n+2) are allowed suprafacially, and 4-electron processes must occur antarafacially (Möbius, 4n). The main pericyclic reactions are classified as follows:


#### **3. Cycloaddition reactions**

non-corrosive properties, which decrease the risk of worker exposure and solvent loss to the atmosphere, make ILs powerful candidates to replace the so-called "volatile organic com‐ pounds" (VOCs) in the development of more environmentally friendly technologies and

Pericyclic reactions belong to a very important group of organic reactions, including some of the most powerful synthetically useful reactions like the Diels-Alder reaction, 1,3-dipolar cycloadditions, the Alder-ene reaction, Cope and Claisen rearrangements, the 2,3-Wittig rearrangement, diimide reduction, sulfoxide elimination, Fisher indole synthesis and many

In the last years, ILs have been employed as reaction media and/or catalysts and co-catalysts to facilitate the curse of many pericyclic reactions. Due to the nature and properties of this kind of compounds, the application of ILs in these reactions has contributed to the development of more efficient and environmentally friendly methodologies. In this chapter, the principles of pericyclic reactions are presented and an overview of the applications of ILs in assisted

The term Pericyclic reactions refers to a set of reactions that are characterized by concert‐ ed processes that proceed via cyclic transition states, which can be interpreted according to the Molecular Orbital Theory. Pericyclic reactions are reactions, where a cyclic, conjugat‐ ed system of electrons is created in the transition state, having highly predictable stereo‐

The stereochemistry of the pericyclic reactions can be predicted based on the principle of conservation of orbital symmetry, employing the rules proposed by Robert Burns Woodward and Ronald Hoffmann in 1965 (Woodward-Hoffmann rules) [6]. This principle applies only to the concerted pericyclic reactions, and in this case, it serves as a powerful predictive tool.

**1.** In an open chain system containing a 4n electron orbital symmetry of the highest occupied molecular orbital of the ground state is such that a bonding interaction between the ends must engage the overlapping between orbital regions in opposite sides of the system, and

**2.** In open systems containing 4n+2 electrons, the terminal binding interaction between molecules in the ground state requires the overlapping regions of the orbitals of the same

**3.** In a photochemical reaction, an electron in the HOMO of the reactant is promoted to an excited state, leading to the reversal of terminal symmetry relations (stereospecificity).

side of the system, and this is attainable only by disrotatory displacements.

The Woodward-Hoffmann rules were established by the authors as:

this can only be achieved through a conrotatory process.

specially for the petroleum industry [3, 4].

4 Ionic Liquids - Current State of the Art

pericyclic reactions is discussed.

**2. Pericyclic reactions**

chemical features [5].

others.

Cycloaddition reactions are the most studied pericyclic reactions, where two or more unsatu‐ rated systems react to give a cycle with one less unsaturation. This reaction allows simultane‐ ous construction of two new carbon-carbon bonds and the formation of cyclic compounds which gave high versatility and applicability in organic synthesis [7]. A typical cycloaddition reaction is the Diels-Alder reaction.

The Diels-Alder (D-A) reaction was discovered and published for the first time in 1928 by Otto Diels and Kurt Alder [8]. This is a thermal, concerted, suprafacial, [4+2] cycloaddition.

In this reaction 1,3-butadiene (diene) reacts with ethylene (dienophile) to give an adduct cyclic product as described in Figure 2. In this kind of reactions, both σ-bonds are formed at the same time, not by steps.

**Figure 2.** An example of cycloaddition reaction.

These reactions proceed according to the following selection rules:

The suprafacial-suprafacial (S-S) reaction geometry is thermally permitted when m+n=4k+2, for example, the Diels-Alder reaction between butadiene and ethylene, where m and n are the number of π electrons (Figure 3).

**Figure 3.** Molecular orbital interaction in a cycloaddition reaction.

Suprafacial (S) means that new bonds are formed on the same face of each reagent, the diene and dienophile. The opposite to suprafacial is antarafacial (A). The term [4+2] refers to a conjugated system of electrons, where a 4- reacts with a 2-electron system.

Figure 3 shows the molecular orbitals (MOs) of 1,3-butadiene and ethylene, and their respec‐ tive relative energies. As noted earlier, the HOMO-LUMO energy gap is greater in ethylene than in butadiene. For the two compounds to react, the HOMO of one must react with the LUMO of the other one with conservation of orbital symmetry. There are two seemingly isoenergetic possibilities, the SS and AA reactions (red arrows), which conserve symmetry. Both energy gaps are equal and too large for a reaction to occur readily.


In the S-S mode, the concerted [4+2] cycloaddition is ground state (thermal) allowed and excited state (h *ϑ*) forbidden, while the [2+2] cycloaddition is just the opposite, ground state forbidden and excited state allowed.

The Diels-Alder reactions involving at least one heteroatom in the dienophile (heterodieno‐ phile) [9] or in the diene (heterodiene) [10] are known as hetero-Diels–Alder reactions. For example, carbonyl groups can react successfully with dienes to yield pyranoid rings, a reaction known as the oxo-Diels-Alder reaction, or when a nitrogen atom can be part of the diene or the dienophile, the reaction is known as aza-Diels-Alder.

**Figure 4.** Molecular orbital interaction in [2+2] reaction.

#### **4. Electrocyclic reactions**

Suprafacial (S) means that new bonds are formed on the same face of each reagent, the diene and dienophile. The opposite to suprafacial is antarafacial (A). The term [4+2] refers to a

ethylene (dienophile )

bonding LUMO

antibonding HOMO

A

S

Figure 3 shows the molecular orbitals (MOs) of 1,3-butadiene and ethylene, and their respec‐ tive relative energies. As noted earlier, the HOMO-LUMO energy gap is greater in ethylene than in butadiene. For the two compounds to react, the HOMO of one must react with the LUMO of the other one with conservation of orbital symmetry. There are two seemingly isoenergetic possibilities, the SS and AA reactions (red arrows), which conserve symmetry.

**1.** One way to reduce the HOMO-LUMO energy gap is by lowering the LUMO of one reactant. This is accomplished by using an "ethylene" that has an electron-withdrawing

**2.** The supra-antara reaction geometry is allowed thermally when m+n=4k, for example, cycloaddition [2+2]. The formation of cyclobutane from two ethylenes cannot be concerted by thermal reaction; the HOMO-LUMO gap requires light (photochemical reaction) for

In the S-S mode, the concerted [4+2] cycloaddition is ground state (thermal) allowed and excited state (h *ϑ*) forbidden, while the [2+2] cycloaddition is just the opposite, ground state

The Diels-Alder reactions involving at least one heteroatom in the dienophile (heterodieno‐ phile) [9] or in the diene (heterodiene) [10] are known as hetero-Diels–Alder reactions. For example, carbonyl groups can react successfully with dienes to yield pyranoid rings, a reaction known as the oxo-Diels-Alder reaction, or when a nitrogen atom can be part of the diene or

conjugated system of electrons, where a 4- reacts with a 2-electron system.

A

S

A

S

butadiene (diene)

**Figure 3.** Molecular orbital interaction in a cycloaddition reaction.

Both energy gaps are equal and too large for a reaction to occur readily.

group attached to it.

LUMO

6 Ionic Liquids - Current State of the Art

HOMO

the excitation of ethylene (Figure 4).

the dienophile, the reaction is known as aza-Diels-Alder.

forbidden and excited state allowed.

Electrocyclic reactions are a type of pericyclic reaction which is unimolecular and in which the termini of a conjugated system become σ bonded to each other to form a shortened π system (Figure 5) [11].

**Figure 5.** Representation of an electrocyclic reaction.

A typical example of this reaction is the electrocyclization of the 1,3,5-hexatriene to the conjugated cyclic diene (Figure 6).

**Figure 6.** Electrocyclization reaction of the 1,3,5-hexatriene.

When there are substituents at the end of an unsaturated system, these substituents have a definite stereochemistry at the cyclic structure depending on the rotation way of the overlap‐ ping molecular orbitals. This relationship might be disrotatory or conrotatory. Fixed geomet‐ rical isomerism imposed upon the open chain is related to rigid tetrahedral isomerism in the cyclic array (Figure 7).

**Figure 7.** Stereochemistry at the cyclic structure depending on the rotation way of the overlapping molecular orbitals.

For this kind of reaction, the thermal reaction is now disrotatory, while the photochemical reaction is conrotatory. According to the Principle of Conservation of Orbital Symmetry by Woodward & Hoffmann [12], the thermal reaction will be conrotatory for 4n systems and disrotatory for 4n+2 systems, and in the opposite way for photochemical reactions.

#### **5. Sigmatropic rearrangements**

In a sigmatropic rearrangement, one bond is broken while another bond is formed across a p system. The numbering system [m, n] gives the number of atoms between the broken bond and the formed bond in both directions [13].

There are two different types of sigmatropic reactions: a) those that involve the migration of a hydrogen atom, and b) those that involve carbon, oxygen or other element atoms. In these reactions, the starting materials are acyclic, but the transition state is cyclic, with pronounced conformational effects. A classical reaction of this type is the Claisen rearrangement (Figure 8). Other typical reactions of this type are the Cope rearrangement and the Fisher indole synthesis.

**Figure 8.** The Claisen rearrangement.

When there are substituents at the end of an unsaturated system, these substituents have a definite stereochemistry at the cyclic structure depending on the rotation way of the overlap‐ ping molecular orbitals. This relationship might be disrotatory or conrotatory. Fixed geomet‐ rical isomerism imposed upon the open chain is related to rigid tetrahedral isomerism in the

B C

B D

**DISROTATORY**

**Figure 7.** Stereochemistry at the cyclic structure depending on the rotation way of the overlapping molecular orbitals.

For this kind of reaction, the thermal reaction is now disrotatory, while the photochemical reaction is conrotatory. According to the Principle of Conservation of Orbital Symmetry by Woodward & Hoffmann [12], the thermal reaction will be conrotatory for 4n systems and

In a sigmatropic rearrangement, one bond is broken while another bond is formed across a p system. The numbering system [m, n] gives the number of atoms between the broken bond

There are two different types of sigmatropic reactions: a) those that involve the migration of a hydrogen atom, and b) those that involve carbon, oxygen or other element atoms. In these reactions, the starting materials are acyclic, but the transition state is cyclic, with pronounced conformational effects. A classical reaction of this type is the Claisen rearrangement (Figure 8). Other typical reactions of this type are the Cope rearrangement and the Fisher indole

disrotatory for 4n+2 systems, and in the opposite way for photochemical reactions.

**CONROTATORY**

A

A

B

D

B

C

cyclic array (Figure 7).

8 Ionic Liquids - Current State of the Art

A

A

**5. Sigmatropic rearrangements**

synthesis.

and the formed bond in both directions [13].

C

D

C

D

Figure 10.In the hydrogen migration, the hydrogen atom can migrate either suprafacially or antarafacially across the conjugated system, leading to Hückel or Möbius topologies for the transition states. The typical migration for these systems is the [1, 5] hydrogen migration (Figure 9).

**Figure 9.** Suprafacial and antarafacial hydrogen migration across the conjugated system.

#### **6. Group transfer reaction**

A group transfer reaction is a process, where one or more groups of atoms are transferred from a molecule to another. Unlike other pericylic reaction classes, group transfer reactions do not have a specific conversion of π-bonds into σ-bonds or vice versa. Typical examples of this process are the ene reaction and the reduction of a double bond by N2H2 diimide reaction, which is a supra-supra reaction involving six electrons.

In the ene reaction, an alkene with an allylic hydrogen (the ene component) reacts with a compound containing a multiple bond (the enophile) like olefins, acetylenes, and benzynes or carbon-hetero multiple bonds such as C=O, C=N, C=S, and C≡P (carbonyl-ene reactions) in order to form a new σ-bond with migration of the ene double bond and 1, 5 hydrogen shift. The product is a substituted alkene with the double bond shifted to the allylic position (Figure 10) [14].

**Figure 10.** The ene reaction.

Due to the principle of microscopic reversibility, there is a parallel set of pericyclic "retro" reactions which perform the reverse reaction: retro Diels-Alder, retro-ene reaction and the retro-electrocyclic reactions. An example of the last one is the reaction in which the trans-3,4 dimethylcyclobutene is cleaved thermally to yield E,E-2,4-hexadiene. In this reaction, the cleavage of a σ-bond occurs to generate a longer conjugated system (Figure 11).

**Figure 11.** Thermal cleavage of the trans-3,4-dimethylcyclobutene.

The cleavage of a σ-bond to generate a longer conjugated system is sometimes called a retroelectrocyclic reaction. As an example of the latter, cyclobutene is cleaved thermally to yield 1,3-butadiene, relieving the extensive strain in the cyclobutene system and gaining the resonance stabilization of the conjugated diene system.

#### **7. IL-assisted cycloaddition reactions**

Cycloaddition is a highly versatile protocol to generate new C-C bonds, being a handy tool for the synthesis of natural products [15, 16].

According to E-Village Compendex [17], in the last decade, 120 papers about IL-assisted cycloaddition reactions have been published with an important increment in the last years (Figure 12).

Among cycloaddition reactions, Diels-Alder reactions are by far the most studied, and also the most studied pericyclic reactions employing ILs. The Diels-Alder reaction is an important class of reaction that allows the synthesis of six-membered rings with accurate control on the

**Figure 12.** Papers published on IL-assisted cycloaddition reactions in the last decade.

**H**

Due to the principle of microscopic reversibility, there is a parallel set of pericyclic "retro" reactions which perform the reverse reaction: retro Diels-Alder, retro-ene reaction and the retro-electrocyclic reactions. An example of the last one is the reaction in which the trans-3,4 dimethylcyclobutene is cleaved thermally to yield E,E-2,4-hexadiene. In this reaction, the

cleavage of a σ-bond occurs to generate a longer conjugated system (Figure 11).

H H

trans-3,4 -dimethylcyclobutene E,E-2,4-hexadiene

The cleavage of a σ-bond to generate a longer conjugated system is sometimes called a retroelectrocyclic reaction. As an example of the latter, cyclobutene is cleaved thermally to yield 1,3-butadiene, relieving the extensive strain in the cyclobutene system and gaining the

Cycloaddition is a highly versatile protocol to generate new C-C bonds, being a handy tool for

According to E-Village Compendex [17], in the last decade, 120 papers about IL-assisted cycloaddition reactions have been published with an important increment in the last years

Among cycloaddition reactions, Diels-Alder reactions are by far the most studied, and also the most studied pericyclic reactions employing ILs. The Diels-Alder reaction is an important class of reaction that allows the synthesis of six-membered rings with accurate control on the

**S-cis**

H H

Ene

Enophile

**Figure 11.** Thermal cleavage of the trans-3,4-dimethylcyclobutene.

resonance stabilization of the conjugated diene system.

**7. IL-assisted cycloaddition reactions**

the synthesis of natural products [15, 16].

(Figure 12).

**Figure 10.** The ene reaction.

10 Ionic Liquids - Current State of the Art

**H**

H

**S-trans**

H

H

H

stereoselectivities of the products. It is well known that the Diels-Alder reaction can be accelerated in the presence of a salt and because of their ionic features, ILs have shown good catalytic properties in this kind of reaction. Considering the environmental pollution provoked by using conventional organic solvents and catalysts, ILs have proved to be alternative solvents and catalysts for carrying out this kind of reactions [18].

Erfurt et al. studied the performance of hydrogen-bond-rich ILs obtained from D-Glucose, where chloroalcohols were used as raw materials and sources of hydroxyl groups for the synthesis of IL cations; bis(trifluoromethylsulfonyl)imide was used as an anion to catalyze the reaction between cyclopentadiene and either diethyl maleate or methyl acrylate. The studied ILs showed high activity even when present in catalytic amounts (4 mol% with respect to dienophile). An increase in the number of hydroxyl groups present in the IL structure resulted in higher reaction rates. The IL tends to form a crystal at temperatures in the range of −29 to −16°C, and is thermally stable from ambient temperature to at least 430°C (Figure 13) [19].

Tamariz and coworkers have studied extensively the synthesis of *exo*-heterocyclic dienes and captodative olephines and their applications in Diels-Alder reactions [20-25]. In one of their works, they studied the effect of several ILs in combination with non-conventional energy sources (microwaves and ultrasound) on this reaction. (Z)-*N*-substituted-4-methylene-5-

**Figure 13.** Diels-Alder cycloaddition using hydrogen-bond-rich ILs obtained from D-Glucose and chloroalcohols as catalysts.

propylidene-2-oxazolidinone dienes were prepared by means of a one-step synthesis, starting from 2,3-hexanedione and isocyanates. Diels-Alder cycloadditions of these dienes were carried out in the presence of dienophile methyl vinyl ketone, methyl propiolate, and a captodative olefin, using high polarity solvents, Lewis acid catalysts, and non-conventional energy sources. The reactions carried out with either H2O/MeOH mixtures or BF3.Et2O catalysts yielded the highest regio-and stereo-selectivities. The use of ILs, microwaves, and ultrasound did not significantly increase the selectivity [26].

Vidis et al., also found a low effect of ultrasound and microwave dielectric heating on the selectivity of Diels-Alder reactions in ILs, but a significant effect on the reaction rate [27].

ILs have also proved to be a powerful reaction medium (or additive) for significant rate acceleration in the Diels-Alder cycloaddition (Figure 14). In this sense, ILs were used as a medium in scandium-triflate-catalysed-Diels-Alder reactions, not only for facilitating the catalyst recovery, but also for accelerating the reaction rate and improving the selectivity [28].

**Figure 14.** Kinetic studies on the reaction between 1,4-naphthoquinone (1 mmol) and 2,3-dimethylbuta-1,3-diene (3 mmol) in the presence of 0.2 mol% of Sc(OTf)3 at 20 °C in methylene chloride and IL (Reproduced from ref. 28 with permission from The Royal Society of Chemistry).

A relatively new class of IL-analogues has been widely explored in the last years with extremely wide application prospects. Compared with conventional organic solvents, deep eutectic solvents (DESs) have more advantages: negligible vapor pressure, non-flammability, good chemical and thermal stability, non-toxicity, biodegradability, recyclability and low price among others [29].

The DES concept was first described by Abbott and coworkers [30], which generally refers to a type of solvent composed of a mixture that forms a eutectic through two cheap and reliable components, which are capable of associating via links, by hydrogen bonding, to a melting point much lower than any of the individual components; a DES can be easily formed by mixing two or more simple components under given operating conditions, manifesting poor conductivity properties. In general, DESs are cheaper than classical ILs, and also feature some other properties that make them very attractive: water-chemical inertness, easy storage, easy preparation (eliminating problems of purification and residue formation), biodegradability and environmentally biocompatibility.

propylidene-2-oxazolidinone dienes were prepared by means of a one-step synthesis, starting from 2,3-hexanedione and isocyanates. Diels-Alder cycloadditions of these dienes were carried out in the presence of dienophile methyl vinyl ketone, methyl propiolate, and a captodative olefin, using high polarity solvents, Lewis acid catalysts, and non-conventional energy sources. The reactions carried out with either H2O/MeOH mixtures or BF3.Et2O catalysts yielded the highest regio-and stereo-selectivities. The use of ILs, microwaves, and ultrasound did not

**Figure 13.** Diels-Alder cycloaddition using hydrogen-bond-rich ILs obtained from D-Glucose and chloroalcohols as

O OH O OH OH HO

N [Tf2N]

CO2Bu <sup>+</sup> <sup>O</sup>

CO2Me

CO2Me

CO2Me

Vidis et al., also found a low effect of ultrasound and microwave dielectric heating on the selectivity of Diels-Alder reactions in ILs, but a significant effect on the reaction rate [27].

ILs have also proved to be a powerful reaction medium (or additive) for significant rate acceleration in the Diels-Alder cycloaddition (Figure 14). In this sense, ILs were used as a medium in scandium-triflate-catalysed-Diels-Alder reactions, not only for facilitating the catalyst recovery, but also for accelerating the reaction rate and improving the selectivity [28].

**Figure 14.** Kinetic studies on the reaction between 1,4-naphthoquinone (1 mmol) and 2,3-dimethylbuta-1,3-diene (3 mmol) in the presence of 0.2 mol% of Sc(OTf)3 at 20 °C in methylene chloride and IL (Reproduced from ref. 28 with

significantly increase the selectivity [26].

+

12 Ionic Liquids - Current State of the Art

catalysts.

O

O

O

permission from The Royal Society of Chemistry).

In most cases, DESs are obtained by mixing a quaternary ammonium salt with metallic salts or species capable of forming bonds by hydrogen bridges. Figure 15 shows a summary of various widely used salts with hydrogen bond donors for the formation of DESs [31].

**Figure 15.** Typical structures of salts and hydrogen bond donors used for the synthesis of DESs.

DESs have shown a very good performance as solvents and catalysts for many organic reactions [32], including Diels-Alder cycloaddition. Particularly, Ilgen and König used DES **1**, obtained from L-carnitine/urea melt, to carry out the D-A reaction between cyclopentadiene and *n*-butylacrylate (Figure 16). The L-carnitine melt shows a very high polarity property to obtain adducts with an excellent yield of 93% with an *endo/exo* selectivity of 3.5/1. High yields (72-95%) were obtained from D-glucose and lactose melt, respectively [33]. These DESs were also used for Heck and Sonogashira cross-couplings and Cu-catalyzed reactions. The 1, 3 dipolar cycloadditions also proceed cleanly in sugar and L-carnitine based melts, but the applicability of L-carnitine melts for standard organic reactions is limited by their lower thermal stability [34].

**Figure 16.** Diels-Alder cycloaddition between cyclopentadiene and *n*-butylacrylate using L-carnitine/urea melt as DES.



(72-95%) were obtained from D-glucose and lactose melt, respectively [33]. These DESs were also used for Heck and Sonogashira cross-couplings and Cu-catalyzed reactions. The 1, 3 dipolar cycloadditions also proceed cleanly in sugar and L-carnitine based melts, but the applicability of L-carnitine melts for standard organic reactions is limited by their lower

> NH2 O

catalyst can be recycled.

acceptor basicity parameters.

that in isooctane.

transformations.

CO2Bu

Several phosphonium-IL-metal chlorides, triflates and bistriflimides catalyzed very efficiently this reaction. The

The second-order rate constants for cycloaddition reaction were determined in various compositions of the IL with water and methanol. Rate reaction constants in pure solvents are in the order of water > [BMIM]BF4 > methanol. Reaction rate constant increases with solvophobicity (Sp), hydrogen-bond donor acidity and hydrogen-bond

The Diels-Alder reaction was studied in a microemulsion (IL-H2O/AOT/isooctane). The apparent second-order rate constants were determined by spectrophotometry.Those in the IL-microemulsion are five times higher than that in isooctane, and *k* 2 in pure IL is at least 10 times higher than

AOT: Sodium bis(2-ethylhexyl)sulfosuccinate.

Significant rate-enhancements for both inter- and intramolecular hetero-Diels−Alder reactions were observed for the reaction in IL- doped CH2Cl2, comparing the standard protocols to the microwave-heated

The acidic chloroaluminate IL can further enhance the catalytic power of an expensive silyl borate catalyst for

*endo exo*

**Observations Ref.**

CO2Bu +

[35]

[36]

[37]

[38]

[39]

thermal stability [34].

14 Ionic Liquids - Current State of the Art

<sup>O</sup> <sup>+</sup>

Trihexyl-

onyl)imide.

1-(1-butyl)-3 methylimidazolium terafluoroborate ([BMIM][BF4])

m

tetradecylphosphoniu

bis(trifluoromethylsulf

Bu

O

**Employed IL Reagents involved in the D-A reaction**

[BMIM][BF4] N-ethylmaleimide and 2,3-

[BMIM][PF6] Functionalized 2(1H)-

[BuPy]Cl:AlCl3((mole fraction) = 0.6

pyrazinones

acrylate

Cyclopentadiene with methyl

Cyclopentadiene and dienophiles from the group of α,β-unsaturated esters, aldehydes and ketones.

Cyclopentadiene and naphthoquinone

dimethyl-1,3-butadiene

N

OH

L -ca rnitine

O O

H2N (**1**) Urea

**Figure 16.** Diels-Alder cycloaddition between cyclopentadiene and *n*-butylacrylate using L-carnitine/urea melt as DES.


**Table 1.** Summary of recent papers studying IL-assisted-D-A reactions.

Another well studied cycloaddition reaction is the one involving the cycloaddition of CO2 with epoxides [47]. The cycloaddition of CO2 is a very important reaction because it allows CO2 fixation, which is a hot topic in current research. The fixation of CO<sup>2</sup> to generate valuable chemicals such as cyclic carbonates is meaningful. Cyclic carbonates are used as polar aprotic solvents, electrolytes in lithium secondary batteries, precursors for the formation of polycar‐ bonates, and intermediates in the production of pharmaceuticals and fine chemicals. Accord‐ ing to studies on this reaction mechanism, the cycloaddition between CO<sup>2</sup> and epoxides catalyzed by ILs takes place through a stepwise mechanism and is not properly a pericyclic reaction [48], however, because of the importance of this reaction, it is briefly discussed here.

In a recent paper, a polymer grafted with an asymmetrical dication, IL-based on imidazolium and phosphonium ([P-Im-C4H8Ph3P]Br2) was synthesized, and for the first time, it was evaluated as a catalyst for the synthesis of cyclic carbonates from epoxides and CO2 without using any co-catalyst and solvent. The catalyst showed higher activity than the monocation imidazolium and phosphonium ILs. At low catalyst loading (0.38 mol%), high yield (96.8%) and selectivity (99.5%) of propylene carbonate can be obtained at 130°C and 2.5 MPa in 4 h. The author proposed that both the nucleophilic attack of bromine anions and their activation could explain the good activity of the catalyst. Furthermore, the catalyst showed excellent stability and reusability. It can be reused for up to five runs without any significant loss of catalytic activity after simple filtration [49].

Very recently, a new method for the synthesis of main chain poly-imidazolium salts (**2**) was developed from bisimidazole and silicon tetrachloride. These types of silicon-based polyimidazolium-salt-poly-ILs were found to be the most efficient metal-free heterogeneous catalysts (TOF=90 h−1) for the fixation of CO2 with epoxides into cyclic carbonates under metaland solvent-free conditions (Figure 17) [50].

**Figure 17.** Synthesis of cyclic carbonates under metal-and solvent-free conditions using silicon-based-poly-imidazoli‐ um-salt-poly-ILs as catalysts.

#### **8. IL-assisted electrocyclic reactions**

**Employed IL Reagents involved in the D-A reaction**

formaldehydes

with enol ether

pyrazolones

A set of cyclic α,β-unsaturated ketones and arylamines with

Heteroarylaldehyde, pyrazolone

*O*-allylated acetophenones/ propiophenone with several 5-

**Table 1.** Summary of recent papers studying IL-assisted-D-A reactions.

1-ethyl-3-

(S)-2-

methylimidazolium-

16 Ionic Liquids - Current State of the Art

pyrrolidinecarboxylic acid salt [EMIM][Pro]

Triethylammonium acetate (TEAA)

Triethylammonium acetate (TEAA)

**Observations Ref.**

[44]

[45]

[46]

The chiral IL catalyzed the one-pot direct asymmetric aza D-A reaction in up to 93% yield with up to >99/1 dr and >99% ee. Moreover, the catalytic system can be recycled and reused six times without any significant loss of

A highly efficient, rapid one-pot procedure has been developed for a three-component domino intermolecular Knoevenagel-intermolecular hetero-Diels-Alder reaction to afforded indolyl- and quinolylpyrano[2,3-c] pyrazoles from corresponding TEAA under microwave irradiation. The reaction advantageously precedes in highly regio- and stereoselective ways in combination with the ease of IL

One-pot procedure for the synthesis of some new angular benzopyrano[3,4-c]pyrano-fused pyrazoles, all of which incorporate a tertiary ring junction carbon by means of domino-Knoevenagel-hetero-Diels-Alder reaction TEAA-mediated one-pot method for the synthesis of a new family of angularly fused polyheterocycles providing efficient and improved reaction conditions for unactivated dienophile propargyl, needing no additional catalyst, required for allyl- and prenyl-based substrates is another

catalytic activity.

recovering.

advantage of this method.

Another well studied cycloaddition reaction is the one involving the cycloaddition of CO2 with epoxides [47]. The cycloaddition of CO2 is a very important reaction because it allows CO2 fixation, which is a hot topic in current research. The fixation of CO<sup>2</sup> to generate valuable chemicals such as cyclic carbonates is meaningful. Cyclic carbonates are used as polar aprotic solvents, electrolytes in lithium secondary batteries, precursors for the formation of polycar‐ bonates, and intermediates in the production of pharmaceuticals and fine chemicals. Accord‐ ing to studies on this reaction mechanism, the cycloaddition between CO<sup>2</sup> and epoxides catalyzed by ILs takes place through a stepwise mechanism and is not properly a pericyclic reaction [48], however, because of the importance of this reaction, it is briefly discussed here.

In a recent paper, a polymer grafted with an asymmetrical dication, IL-based on imidazolium and phosphonium ([P-Im-C4H8Ph3P]Br2) was synthesized, and for the first time, it was evaluated as a catalyst for the synthesis of cyclic carbonates from epoxides and CO2 without using any co-catalyst and solvent. The catalyst showed higher activity than the monocation imidazolium and phosphonium ILs. At low catalyst loading (0.38 mol%), high yield (96.8%) and selectivity (99.5%) of propylene carbonate can be obtained at 130°C and 2.5 MPa in 4 h.

ILs are also a very useful option for the development of electrocyclic reactions. Some examples of this reaction using ILs will be discussed below.

The use of microwaves as conventional heating source to carry out chemical reactions is very useful for obtaining high yields of products with short reaction times. In recent years, many reactions have been reported, where the use of microwaves as a heating source and ILs as solvents or catalysts for reactions has been combined. Because of their ionic nature, ILs are heated very quickly when subjected to microwave irradiation. This is an excellent feature to perform very rapid and efficient reactions that match the "green concept" [51-53].

In 2012, Freneda and Blazquez studied the synthesis of β-carbolines (pyrido[3,4-*b*]indole) using the microwave-assisted-tandem-aza-Wittig/electrocyclic-ring-closure methodology in ILs. This efficient procedure using microwave irradiation in combination with the IL [BMIM][BF4] used as the solvent was useful for the preparation of aryl/aroyl-1-substituted-9H-pyrido[3,4 *b*]indoles (Figure 18).

The pyrido-annulation process involved the simultaneous deprotection of an *N*-methoxy‐ methyl group using IL/microwave-assisted irradiation with good yields (65–90%) and short reaction times (15–25 min) as shown in Table 2 [54].

**Figure 18.** Synthesis of β-carbolines (pyrido[3,4-*b*]indole) using the microwave-assisted tandem-aza-Wittig/electrocy‐ clic-ring-closure methodology in ILs.


**Table 2.** Time and yields of β-carboline synthesis using microwave-assisted-tandem-aza-Wittig/electrocyclic-ringclosure methodology in [BMIM][BF4].<sup>a</sup>

#### **9. IL-assisted sigmatropic rearrangements**

Another useful application of ILs in organic syntheses is as soluble supports to immobilize certain organic substrates. The high polarity and ionic character of IL supports have proved to exert synergistic effects and reaction rate enhancements.

Dihydropyrimidine and benzimidazole derivatives are key structural elements in many biologically active natural products and pharmaceutical compounds. Some of them constitute key intermediates which have widespread applications in drug research. Recently, an efficient IL-supported synthesis of novel benzimidazole-fused-dihydropyrimidine derivatives cata‐ lyzed by Lewis bases was published.

3-Hydroxyethyl-1-methylimidazolium tetrafluoroborate, as an ionic soluble IL support, was employed for immobilizing 2-amino benzo[*d*]imidazole. Twenty primary amines and alde‐ hydes were evaluated in this parallel protocol, furnishing the products with high purity and yields (72-98%) (Figure 19).

**Figure 19.** One-pot parallel synthesis of [1,5]-sigmatropic rearrangement involving immobilized 2-amino benzo[*d*]imi‐ dazole.

**R-CHO R-COCH(OH)2 Time (min) Yield (%)** 4-MeOC6H4 15 79 4-ClC6H4 20 70 C6H5 20 73 C6H5-(CH2)2 20 65

**Figure 18.** Synthesis of β-carbolines (pyrido[3,4-*b*]indole) using the microwave-assisted tandem-aza-Wittig/electrocy‐

R-CHO or R-COCH(OH)2

**Table 2.** Time and yields of β-carboline synthesis using microwave-assisted-tandem-aza-Wittig/electrocyclic-ring-

Another useful application of ILs in organic syntheses is as soluble supports to immobilize certain organic substrates. The high polarity and ionic character of IL supports have proved

Dihydropyrimidine and benzimidazole derivatives are key structural elements in many biologically active natural products and pharmaceutical compounds. Some of them constitute key intermediates which have widespread applications in drug research. Recently, an efficient IL-supported synthesis of novel benzimidazole-fused-dihydropyrimidine derivatives cata‐

3-Hydroxyethyl-1-methylimidazolium tetrafluoroborate, as an ionic soluble IL support, was employed for immobilizing 2-amino benzo[*d*]imidazole. Twenty primary amines and alde‐ hydes were evaluated in this parallel protocol, furnishing the products with high purity and

a

(R-CHO/ R-COCH(OH)2): 1:1, MW, power: 1 W, T: 200°C.

**9. IL-assisted sigmatropic rearrangements**

to exert synergistic effects and reaction rate enhancements.

closure methodology in [BMIM][BF4].<sup>a</sup>

N

18 Ionic Liquids - Current State of the Art

clic-ring-closure methodology in ILs.

N=PPh3

CO2Et

O

lyzed by Lewis bases was published.

yields (72-98%) (Figure 19).

C6H5 15 88 4-MeOC6H4 15 90 N-MOM-indol-3-yl 25 76

N H

X=R X = COR N

CO2Et

X

The novel multicomponent reaction between IL-anchored, 2-aminobenzoimidazoles, alde‐ hydes, and electron-deficient dienophiles, described below, involve a [1,5]-sigmatropic rearrangement, which was compatible with a wide range of substrates to furnish the new scaffolds. The use of the IL as a soluble support facilitates purification by simple precipitation along with advantages such as high loading capacity, homogeneous reaction conditions and monitoring of the reaction progress by conventional NMR spectroscopy [55].

In 2011, an example of [2,3]-sigmatropic rearrangement was published, showing the cyclo‐ propanation of 5-(allyloxymethyl)-and 5-(methallyloxymethyl)-5-ethyl-1,3-dioxanes with methyl diazoacetate catalyzed by Rh2OAc4 or Cu(OTf)2 in the presence of [BMIM]Cl, [BMIM]BF4 and [BMIM]PF6, which proceeded regioselectively at the C=C bond and led to the formation of the corresponding cyclopropane-containing 1,3-dioxanes in yields up to 62% [56].

In another example of [2,3]-sigmatropic rearrangement, an efficient enantioselective approach towards the construction of quaternary indolizidines from proline building block co-catalyzed by the IL 1-butyl-3-methylimidazolium hexafluorophosphate was shown. In this work, the author explored N → C chirality transfer under [2,3]-shift of a proline derivative ammonium, yielding stereogenic at nitrogen. The rearrangement was stereospecific because the [2,3] migrations were restricted to the same face, and the stereoselectivity arose from the previous N-alkylation step. A mechanism was proposed in which the use of an IL showed an improve‐ ment in the yields of the Stevens rearrangement due to a possible stabilization and/or activation of zwiterionic species in solution by the IL (Figure 20) [57].

Another type of sigmatropic rearrangement explored with the assistance of an IL is the [3,3] sigmatropic rearrangement involved in the Fisher indole synthesis.

Widespread occurrence of indoles in natural products and biologically active compounds has led to a continued interest in the practical synthesis of the indole nucleus. Despite the diverse and creative approaches that have been developed so far, the classical Fischer indole synthetic methodology, which involves hydrazone formation and subsequent [3,3]-sigmatropic rear‐ rangement remains the benchmark method.

**Figure 20.** Proposed mechanism for IL stabilization of zwiterionic species in the Stevens [2,3]-sigmatropic rearrange‐ ment.

Calderon-Morales et al. carried out the one-pot conversion of phenylhydrazine and ketone to the indole. The Fischer indole synthesis with one equivalent of the IL Choline chloride 2ZnCl2 (ChCl2⋅ZnCl2) with direct product isolation by vacuum sublimation was used. Since an IL has very low vapor pressure, then the vapor pressure of the solution of the indole product in the IL would be expected to be about the same as the vapor pressure of the indole itself. Following this procedure, ten indole derivatives were obtained in high yield with one equivalent of ChCl2⋅ZnCl2; exclusive formation of 2,3-disubstituted indoles is observed in the reaction of alkyl methyl ketones, and the products readily sublime directly from the IL. For example, in the case of 2-phenylindole, a 91% yield of product could be obtained by direct vacuum sublimation of the IL reaction mixture, while for 2,3-dimethylindole, a 56% yield was obtained, using this method. In unsymmetrical cases, regiospecific formation of a single product arising from the formation of the most substituted enamine intermediate is observed (Figure 21) [58].

$$\left| \underbrace{\sum\_{s}^{s} \bigotimes\_{\mu} s}\_{\#} \right| \ll \sum\_{\mu} \sum\_{\mu \atop \#} \left[ \sum\_{s}^{s} \bigotimes\_{\mu} s \right] \ll \sum\_{\mu \atop \#} \sum\_{s^{\otimes}} \ll \sum\_{\mu \vdash \#} \sum\_{\mu \vdash \#} \left[ \sum\_{s^{\otimes} \mid \#} s \right]$$

**Figure 21.** Fischer indole synthesis using ChCl 2ZnCl2.

The Fischer indole synthesis of different ketones using chloroaluminate IL as a solvent as well as a catalyst has been also described [59].

#### **10. IL-assisted group transfer reactions**

The ene reaction has been one of the most explored group transfer reactions using Ils. Gore et al., reported, in 2013, a tandem ionic liquid asymmetric catalysis study: carbonyl-ene reactions with trifluoropyruvate with five alkenes catalysed by [Pd{(*R*)-BINAP}](SbF6)2 were carried out. The synthesized and evaluated ILs showed low antimicrobial toxicity. Excellent yields and enantioselectivities (up to 96% yield and 94% ee) were obtained using IL (**X**) as a solvent. These results were either superior or comparable to those associated with conventional volatile solvents (*e.g.* CH2Cl2). Substrate scope studies revealed identical enantioselectivity when using methylenecyclopentane in either IL **4** or CH2Cl2. Furthermore, the IL **4** immobilized catalyst [Pd{(*R*)-BINAP}](SbF6)2 reaction medium was recycled and reused up to 7 times without losing activity (Figure 22) [60].

**Figure 22.** Enantioselective carbonyl-ene reaction using the IL (**X**) as solvent.

Calderon-Morales et al. carried out the one-pot conversion of phenylhydrazine and ketone to the indole. The Fischer indole synthesis with one equivalent of the IL Choline chloride 2ZnCl2 (ChCl2⋅ZnCl2) with direct product isolation by vacuum sublimation was used. Since an IL has very low vapor pressure, then the vapor pressure of the solution of the indole product in the IL would be expected to be about the same as the vapor pressure of the indole itself. Following this procedure, ten indole derivatives were obtained in high yield with one equivalent of ChCl2⋅ZnCl2; exclusive formation of 2,3-disubstituted indoles is observed in the reaction of alkyl methyl ketones, and the products readily sublime directly from the IL. For example, in the case of 2-phenylindole, a 91% yield of product could be obtained by direct vacuum sublimation of the IL reaction mixture, while for 2,3-dimethylindole, a 56% yield was obtained, using this method. In unsymmetrical cases, regiospecific formation of a single product arising from the formation of the most substituted enamine intermediate is observed

**Figure 20.** Proposed mechanism for IL stabilization of zwiterionic species in the Stevens [2,3]-sigmatropic rearrange‐

NN <sup>+</sup>

CO2Me

Bu

[2,3]-shift <sup>N</sup>

Ph

CO2Me

N

Ph

PF6

NH2 N

The Fischer indole synthesis of different ketones using chloroaluminate IL as a solvent as well

The ene reaction has been one of the most explored group transfer reactions using Ils. Gore et al., reported, in 2013, a tandem ionic liquid asymmetric catalysis study: carbonyl-ene reactions with trifluoropyruvate with five alkenes catalysed by [Pd{(*R*)-BINAP}](SbF6)2 were carried out. The synthesized and evaluated ILs showed low antimicrobial toxicity. Excellent yields and enantioselectivities (up to 96% yield and 94% ee) were obtained using IL (**X**) as a solvent. These results were either superior or comparable to those associated with conventional volatile

H <sup>N</sup> R1

R2

R3

H

R1 R3

R2

(Figure 21) [58].

<sup>N</sup> CO2Me

20 Ionic Liquids - Current State of the Art

Ph

ment.

base [BMIM]PF6

N H R2

**Figure 21.** Fischer indole synthesis using ChCl 2ZnCl2.

as a catalyst has been also described [59].

**10. IL-assisted group transfer reactions**

R3

ChCl.2ZnCl2

R1 <sup>+</sup> <sup>N</sup>

O

In 2012, Kim et al. reported an optimal hydrophobic IL as a solvent for highly enantioselectiveglyoxylate-ene reactions catalyzed by a chiral bis(oxazoline)-copper complex. [BMIM] with BF4, PF6, OTf and SbF2 were evaluated as solvents. The reactivity and stereoselectivity were highly dependent upon the properties of the IL, being the last one the best IL according to the yield (93%) and selectivity (94% *e/e*). Reactions between olefins and ethyl glyoxylate in [BMIM]SbF6 at ambient temperature provided remarkably enhanced reactivity and stereose‐ lectivity, which greatly exceed those of the corresponding reactions in dichloromethane. Furthermore, the metal-ligand complex was readily recycled up to eight times, while exhibit‐ ing no significant decrease in reaction efficiency (Figure 23) [61].

**Figure 23.** Catalytic enantioselective ene reaction of α-methyl styrene and ethyl glyocylate with the cupper complex as catalyst and IL as solvent.

Very recently, the synthesis of ILs using the ene pericyclic reaction was also described. In this interesting work, a series of new lipid-inspired ILs was synthesized through thiolene "click" reaction with a single-step process. This synthesis offers considerable promise as an efficient and orthogonal method to construct structurally diverse imidazolium-type ILs with linear and branched cationic tails, as well as versatility in the placement of the sulfur heteroatom. Profound solvent effect on this ene-reaction regioselectivity has been observed (Figure 24) [62].

**Figure 24.** Synthesis of lipid-inspired ILs through thiol-ene "click" reaction as a single-step process.

#### **11. Conclusions**

As seen through this chapter, ionic liquids offer a great potential for the development of pericyclic reactions. Ionic liquids have shown to be powerful as catalysts, cocatalysts, solvents and additives in these reactions and in most cases, highly improved results regarding the yields and reaction rates have been observed and in the case of chiral reactions, excellent enantiomeric excesses have also been found. So far, in the case of cycloaddition reactions and particularly for the Diels-Alder reaction the results are very abundant, however, these are still scarce for the rest of pericyclic reactions. Both the results obtained so far and research trends are aimed at developing new methods featuring high efficiency and more environmental suitability with the use of ILs.

#### **Author details**

Rafael Martínez-Palou1 , Octavio Olivares-Xometl2 , Natalya V. Likhanova1 and Irina Lijanova3

1 Dirección de Investigación y Posgrado. Instituto Mexicano del Petróleo. México D.F., México

2 Benemérita Universidad Autónoma de Puebla, Facultad de Ingeniería Química, Col. San Manuel, Ciudad Universitaria. Puebla Puebla, México

3 Instituto Politécnico Nacional, CIITEC, Cerrada Cecati S/N, Colonia Santa Catarina, Azca‐ potzalco, México D.F., México

#### **References**

NTf2

product

n S R

h MeOH

22 Ionic Liquids - Current State of the Art

NTf2

**11. Conclusions**

the use of ILs.

**Author details**

Irina Lijanova3

Rafael Martínez-Palou1

potzalco, México D.F., México

NN

NN <sup>+</sup> <sup>R</sup>

n = 1, 3, 5, 6 R=C7, C8, C10, C1 2

**Figure 24.** Synthesis of lipid-inspired ILs through thiol-ene "click" reaction as a single-step process.

, Octavio Olivares-Xometl2

Manuel, Ciudad Universitaria. Puebla Puebla, México

n

SH

h

NTf2

, Natalya V. Likhanova1

and

n S

R

NN

MeOH/CH2Cl2 Markovnikov

As seen through this chapter, ionic liquids offer a great potential for the development of pericyclic reactions. Ionic liquids have shown to be powerful as catalysts, cocatalysts, solvents and additives in these reactions and in most cases, highly improved results regarding the yields and reaction rates have been observed and in the case of chiral reactions, excellent enantiomeric excesses have also been found. So far, in the case of cycloaddition reactions and particularly for the Diels-Alder reaction the results are very abundant, however, these are still scarce for the rest of pericyclic reactions. Both the results obtained so far and research trends are aimed at developing new methods featuring high efficiency and more environmental suitability with

1 Dirección de Investigación y Posgrado. Instituto Mexicano del Petróleo. México D.F., México

3 Instituto Politécnico Nacional, CIITEC, Cerrada Cecati S/N, Colonia Santa Catarina, Azca‐

2 Benemérita Universidad Autónoma de Puebla, Facultad de Ingeniería Química, Col. San

*anti*-Markovnikov product


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### **Chapter 2**

## **Heck Coupling in Ionic Liquids**

Ahmed Al Otaibi, Christopher P. Gordon and Adam McCluskey

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/59089

#### **1. Introduction**

Synthetic and medicinal chemistry intersect at the production of compounds. However there are stark contracts in approach with synthetic chemistry typically producing complex molecules and developing synthetic approaches. In medicinal chemistry, the focus is on compound access to facilitate compound screening and structure activity data acquisition to enable the synthesis of more active compounds. Medicinal chemistry relies on a small range of highly robust and reliable reactions to gain access to a wide array of potentially bioofi‐ cal reactions.[1, 2]

This reliance on rebust chemistries has been significantly enhanced through the development of efficient C-C coupling protocols, in particular the coupling of aryl halides with α,βunsaturated building block. The power of these new coupling technologies has been reflected in the recent Nobel prizes in this area to Heck,[3] Suzuki,[4] Grubb and their co-workers.[5]

While the development of new methodologies is of paramount importance across all areas of synthetic chemistry, simple developments and increased understanding of reaction conditions and reaction media often enhance these new methodologies. In this latter regard the growth of knowledge in and around room temperature ionic liquids and and their ability to moderate reaction outcomes through their tuneable nature and ability to act as solvents for a wide range of chemical compounds has proved, arguably, equally important. Importantly, the combina‐ tion of developments in C-C coupling technology and RTILs has allowed enhancement in the overall process efficiency. That is, these processes are becoming more environmentally sustainable.

Our group's primary focus requires rapid access to focused compound libraries of bioactive molecules spanning multiple potential therapeutic targets: the inhibition of dynamin GTPase, protein phosphatases 1A and 2A and the development of anti-cancer lead compounds.[6-12]

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Where possible we are keen to apply green chemistry principles around reagent, solvent and synthetic pathway choice.[13-16] Within our own research efforts we have routinely tolerated low yields and difficult purifications to gain access to the desired compounds.[17, 18] We have thus invested considerable resources in the examination, and application, of RTILs and other emerging technologies to the synthesis of bioactive focused compound libraries.[19-23] A current program focus within our team is the development of robust flow and microwave approaches to Pd-mediated C-C coulpling reactions, especially the Heck-Mizoroki (Heck reaction).

#### **1.1. The Heck–Mizoroki reaction (the Heck reaction)**

The cross-coupling of organic halides with alkenes in the presence of catalytic quantities of Pd(0) and a base was first reported by Mizoroki and Heck in 1971.[24, 25] Over the next four decades this has become known as "the Heck reaction" and has been the subject of a number of synthetic and mechanistic studies. It is now generally accepted that there are four key requirements / conditions to a successful Heck coupling reaction: 1) *Solvent*: The Heck reaction generally requires a polar solvent such as dimethyl formamide (DMF) and dimethyl sulfoxide (DMSO); 2) *Base*: The Heck reaction bases are usually selected from Et3N, NaOAc or aqueous Na2CO3 or NaHCO3;[26] 3) *Catalyst*: The Heck reaction uses 1-5 mol% catalytic palladium (0) or palladium (II) complexes. Most commonly in the form of Pd(0)-phosphine complexes such as tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] or dibenzylidene-acetone complexes of Pd(0) such as Pd2(dba)3(dba).[27] Simple palladium salts such as PdCl2 or Pd(OAc)2 in the absence of stabilizing phosphine ligands have also been widely used.[28]- [30] 4) *Halide*: The reactivity of the halide precursor effects the time and temperature required to effect the desired coupling reaction (Figure 1). also been widely used.[28]-[30] 4) *Halide*: The reactivity of the halide precursor effects the time and temperature required to

effect the desired coupling reaction (Figure 1).

Figure 1. General reaction scheme of a Heck cross coupling between an aryl and an olefin indicating the four key variables: base, solvent, catalyst and temperature. **Figure 1.** General reaction scheme of a Heck cross coupling between an aryl and an olefin indicating the four key varia‐ bles: base, solvent, catalyst and temperature.

#### **2. Heck reaction in Room Temperature Ionic Liquids (RTILs) 2. Heck reaction in Room Temperature Ionic Liquids (RTILs)**

The emergence of room temperature ionic liquids (RTILs) has allowed the investigation of the Heck reaction in a wide The emergence of room temperature ionic liquids (RTILs) has allowed the investigation of the Heck reaction in a wide range of novel and tuneable solvents systems.

range of novel and tuneable solvents systems. These novel solvents cover a wide range of structural moiefs from the now well established methylimidazolium and pyridinium salts through ammonium and phosphonium based systems. RTILs now comprise a wide arry of sub classes including protic (PILs), basic (BILs), chiral (CILs), solid supported (SLIPs) and functionalised (FIL).[31, 32] Key examples of these

catalysts are also shown in Figure 2.

**2.1. Imidazolium and pyridinium RTILs** 

efficiency of the chloride analogues (Table 1).[33]

Figure 2. Selected examples of ionic liquids and Pd-catalysts used in the Heck reaction.

These novel solvents cover a wide range of structural moiefs from the now well established methylimidazolium and pyridinium salts through ammonium and phosphonium based systems. RTILs now comprise a wide arry of sub classes including protic (PILs), basic (BILs), chiral (CILs), solid supported (SLIPs) and functionalised (FIL).[31],[32] Key examples of these systems are shown in Figure 2. The custom design nature of these RTILs modifies their ability to solubulise materials and affects the outcome of a wide range of chemical transformations. Herein our focus is the Heck reaction. In addition to the variable nature of the RTIL, a number of novel Pd-catalysts have been developed to enhance the Heck coupling outcomes, especially with the use of deactivated aryl halides and olefins. Selected examples of these Pd-

The coupling efficiency of ethyl acrylate with iodobenzene mediated by Pd(OAc)2 was examined in the presence of *N*hexylpyridinium [*N*-C6H13Py][X], where X = Cl, PF6 and BF4, and with [bmim][PF6] and 1-pentyl-3-methylimidazolium chloride ([pmim]Cl) RTILs (Scheme 1). The *N*-C6H13Py systems afforded higher yields of the coupled product, *E*-ethyl cinnamate, than the equivalent [bmim]Cl. Similarly, a higher coupling yield was obtained with [*N*-C6H13Py][BF4] than [*N*-C6H13Py][PF6], but required higher reactions temperatures 80 °C and extended reaction durations of 72 h to attain the also been widely used.[28]-[30] 4) *Halide*: The reactivity of the halide precursor effects the time and temperature required to

The emergence of room temperature ionic liquids (RTILs) has allowed the investigation of the Heck reaction in a wide

systems are shown in Figure 2. The custom design nature of these RTILs modifies their ability to solubulise materials and affects the outcome of a wide range of chemical transformations. Herein our focus is the Heck reaction. In addition to the variable nature of the RTIL, a number of novel Pd-catalysts have been developed to enhance the Heck coupling outcomes, especially with the use of deactivated aryl halides and olefins. Selected examples of these Pd-catalysts are also shown in Figure 2. Figure 1. General reaction scheme of a Heck cross coupling between an aryl and an olefin indicating the four key variables: base, solvent, catalyst and temperature. **2. Heck reaction in Room Temperature Ionic Liquids (RTILs)** 

effect the desired coupling reaction (Figure 1).

range of novel and tuneable solvents systems.

These novel solvents cover a wide range of structural moiefs from the now well established methylimidazolium and **Figure 2.** Selected examples of ionic liquids and Pd-catalysts used in the Heck reaction.

#### pyridinium salts through ammonium and phosphonium based systems. RTILs now comprise a wide arry of sub classes including protic (PILs), basic (BILs), chiral (CILs), solid supported (SLIPs) and functionalised (FIL).[31],[32] Key examples of **2.1. Imidazolium and pyridinium RTILs**

efficiency of the chloride analogues (Table 1).[33]

Where possible we are keen to apply green chemistry principles around reagent, solvent and synthetic pathway choice.[13-16] Within our own research efforts we have routinely tolerated low yields and difficult purifications to gain access to the desired compounds.[17, 18] We have thus invested considerable resources in the examination, and application, of RTILs and other emerging technologies to the synthesis of bioactive focused compound libraries.[19-23] A current program focus within our team is the development of robust flow and microwave approaches to Pd-mediated C-C coulpling reactions, especially the Heck-Mizoroki (Heck

The cross-coupling of organic halides with alkenes in the presence of catalytic quantities of Pd(0) and a base was first reported by Mizoroki and Heck in 1971.[24, 25] Over the next four decades this has become known as "the Heck reaction" and has been the subject of a number of synthetic and mechanistic studies. It is now generally accepted that there are four key requirements / conditions to a successful Heck coupling reaction: 1) *Solvent*: The Heck reaction generally requires a polar solvent such as dimethyl formamide (DMF) and dimethyl sulfoxide (DMSO); 2) *Base*: The Heck reaction bases are usually selected from Et3N, NaOAc or aqueous Na2CO3 or NaHCO3;[26] 3) *Catalyst*: The Heck reaction uses 1-5 mol% catalytic palladium (0) or palladium (II) complexes. Most commonly in the form of Pd(0)-phosphine complexes such as tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] or dibenzylidene-acetone complexes of Pd(0) such as Pd2(dba)3(dba).[27] Simple palladium salts such as PdCl2 or Pd(OAc)2 in the

reactivity of the halide precursor effects the time and temperature required to effect the desired

**Figure 1.** General reaction scheme of a Heck cross coupling between an aryl and an olefin indicating the four key varia‐

effect the desired coupling reaction (Figure 1).

range of novel and tuneable solvents systems.

The emergence of room temperature ionic liquids (RTILs) has allowed the investigation of the

These novel solvents cover a wide range of structural moiefs from the now well established methylimidazolium and pyridinium salts through ammonium and phosphonium based systems. RTILs now comprise a wide arry of sub classes including protic (PILs), basic (BILs), chiral (CILs), solid supported (SLIPs) and functionalised (FIL).[31, 32] Key examples of these

catalysts are also shown in Figure 2.

**2.1. Imidazolium and pyridinium RTILs** 

efficiency of the chloride analogues (Table 1).[33]

[30] 4) *Halide*: The

Figure 1. General reaction scheme of a Heck cross coupling between an aryl and an olefin indicating the four key variables: base,

These novel solvents cover a wide range of structural moiefs from the now well established methylimidazolium and pyridinium salts through ammonium and phosphonium based systems. RTILs now comprise a wide arry of sub classes including protic (PILs), basic (BILs), chiral (CILs), solid supported (SLIPs) and functionalised (FIL).[31],[32] Key examples of these systems are shown in Figure 2. The custom design nature of these RTILs modifies their ability to solubulise materials and affects the outcome of a wide range of chemical transformations. Herein our focus is the Heck reaction. In addition to the variable nature of the RTIL, a number of novel Pd-catalysts have been developed to enhance the Heck coupling outcomes, especially with the use of deactivated aryl halides and olefins. Selected examples of these Pd-

The coupling efficiency of ethyl acrylate with iodobenzene mediated by Pd(OAc)2 was examined in the presence of *N*hexylpyridinium [*N*-C6H13Py][X], where X = Cl, PF6 and BF4, and with [bmim][PF6] and 1-pentyl-3-methylimidazolium chloride ([pmim]Cl) RTILs (Scheme 1). The *N*-C6H13Py systems afforded higher yields of the coupled product, *E*-ethyl cinnamate, than the equivalent [bmim]Cl. Similarly, a higher coupling yield was obtained with [*N*-C6H13Py][BF4] than [*N*-C6H13Py][PF6], but required higher reactions temperatures 80 °C and extended reaction durations of 72 h to attain the

**2. Heck reaction in Room Temperature Ionic Liquids (RTILs)** 

Figure 2. Selected examples of ionic liquids and Pd-catalysts used in the Heck reaction.

absence of stabilizing phosphine ligands have also been widely used.[28]-

solvent, catalyst and temperature.

**2. Heck reaction in Room Temperature Ionic Liquids (RTILs)**

Heck reaction in a wide range of novel and tuneable solvents systems.

bles: base, solvent, catalyst and temperature.

reaction).

30 Ionic Liquids - Current State of the Art

**1.1. The Heck–Mizoroki reaction (the Heck reaction)**

The emergence of room temperature ionic liquids (RTILs) has allowed the investigation of the Heck reaction in a wide these systems are shown in Figure 2. The custom design nature of these RTILs modifies their ability to solubulise materials and affects the outcome of a wide range of chemical transformations. Herein our focus is the Heck reaction. In addition to the variable nature of the RTIL, a number of novel Pd-catalysts have been developed to enhance the Heck coupling outcomes, especially with the use of deactivated aryl halides and olefins. Selected examples of these Pdcatalysts are also shown in Figure 2. **2.1. Imidazolium and pyridinium RTILs**  The coupling efficiency of ethyl acrylate with iodobenzene mediated by Pd(OAc)2 was examined in the presence of *N*-hexylpyridinium [*N*-C6H13Py][X], where X=Cl, PF6 and BF4, and with [bmim][PF6] and 1-pentyl-3-methylimidazolium chloride ([pmim]Cl) RTILs (Scheme 1). The *N*-C6H13Py systems afforded higher yields of the coupled product, *E*-ethyl cinnamate, than the equivalent [bmim]Cl. Similarly, a higher coupling yield was obtained with [*N*-C6H13Py] [BF4] than [*N*-C6H13Py][PF6], but required higher reactions temperatures 80 °C and extended reaction durations of 72 h to attain the efficiency of the chloride analogues (Table 1).[33]

> The coupling efficiency of ethyl acrylate with iodobenzene mediated by Pd(OAc)2 was examined in the presence of *N*hexylpyridinium [*N*-C6H13Py][X], where X = Cl, PF6 and BF4, and with [bmim][PF6] and 1-pentyl-3-methylimidazolium chloride ([pmim]Cl) RTILs (Scheme 1). The *N*-C6H13Py systems afforded higher yields of the coupled product, *E*-ethyl cinnamate, than the equivalent [bmim]Cl. Similarly, a higher coupling yield was obtained with [*N*-C6H13Py][BF4] than [*N*-C6H13Py][PF6], but required higher reactions temperatures 80 °C and extended reaction durations of 72 h to attain the

Figure 2. Selected examples of ionic liquids and Pd-catalysts used in the Heck reaction.

Sheme 1.Reagents and conditions: 2 mol % Pd(OAc)2, a RTIL (see Table 1 for detail), Et3N or NaHCO3, 40-100 ºC, 24-72 h. **Sheme 1.** Reagents and conditions: 2 mol % Pd(OAc)2, a RTIL (see Table 1 for detail), Et3N or NaHCO3, 40-100 °C, 24-72 h.

**RTIL Base Temp. °C Time (h) Yield %** 

good yields of the Heck coupling product (Scheme 2). Product isolation was by extraction allowing direct reuse of the

Arene diazonium salts in RTILs have proved to be viable alternatives to aryl bromides and iodides in Pd-mediated couplings.[36],[37] In [bmim][PF6], arene diazonium BF4 salts were readily coupled with acrylonitrile, but vinyl ethers and esters were less reactive requiring more forcing conditions of higher temperature and longer reaction duration (Scheme


coupling of the less reactive 4-bromoanisole where the effect of group 15 ligands was also explored and showed enhanced yields relative to the classical approach. The RTILs [*N*-C6H13Py][Cl] and [bmim][BF4] allowed the facile **Table 1.** Heck coupling of iodobenzene and ethyl acrylate to give *E*-ethyl cinnamate in *N*-hexylpyridinium and methylimidazolium RTILs and 2 mol% Pd(OAc)2.

coupling of benzoic anhydride (as the aryl moiety source) and butyl acrylate giving *trans-*butyl cinnamate in 90-95%. This coupling was conducted at 160 °C with [*N*-C6H13Py][Cl] and PdCl2, and 200 ºC with [bmim][BF4] and Pd(OAc)2 and P(*o*-tol)3. [33] Xiao *et al* noted that [bmim][BF4] promoted the ionic pathway in the arylation of electron-rich olefins affording high -regioselectivity (Table 2).[34] **ILs Aryl halide Temp. °C Halide conversion %**  [bmim][Br] iodobenzenea 90 94 4-bromobenzaldehydeb 100 71 [bmim][BF4] iodobenzenea 90 35 4-bromobenzaldehydeb 100 3 The imidazolium RTILs gave low coupling yield in the absence of phosphine ligands. Addition of Ph3P to [bmim][PF6] saw a significant rise in *E*-ethyl cinnamate yield to 99%, and this system could be re-used six times with no observable loss in catalyst activity. Pure product was obtained directly via hexane extraction. This approach was also suitable for coupling of the less reactive 4-bromoanisole where the effect of group 15 ligands was also explored and showed enhanced yields relative to the classical approach. The RTILs [*N*-C6H13Py][Cl] and [bmim][BF4] allowed the facile coupling of benzoic anhydride (as the aryl moiety source) and butyl acrylate giving *trans-*butyl cinnamate in 90-95%. This coupling was conducted at 160 °C with [*N*-C6H13Py][Cl] and PdCl2, and 200 °C with [bmim][BF4] and Pd(OAc)2 and P(*o*-tol)3.[33] Xiao *et al* noted that [bmim][BF4] promoted the ionic pathway in the arylation of electron-rich olefins affording high α-regioselectivity (Table 2).[34]

Table 2. Selected results for Heck reaction between the listed arylhalides and ethyl acrylate or butyl acrylate in [Bmim]Br and [Bmim]BF4. a reaction with ethyl acrylate, b reaction with butyl acrylate. Yokoyama showed that heating an aryl substrate, olefin and 3 mol% of 10% Pd/C dispersed in [bmim][PF6] afforded Yokoyama showed that heating an aryl substrate, olefin and 3 mol% of 10% Pd/C dispersed in [bmim][PF6] afforded good yields of the Heck coupling product (Scheme 2). Product isolation was by extraction allowing direct reuse of the RTIL and catalyst without loss of coupling efficiency.[35]

RTIL and catalyst without loss of coupling efficiency.[35]

3).[38]

Sheme 2.Reagents and conditions: 3 mol % Pd/C (10%) / [bmim][PF6], Et3N, .

[33] Xiao *et al* noted that [bmim][BF4] promoted the ionic pathway in the arylation of electron-rich olefins

The use of more substituted *o*-iodoaryl allyl ethers using the above approach allowed rapid access to 3-substituted

Specialty highly recyclable Pd-complexes, such as Alper's Pd(II)-bisimidazole (Scheme 6), have proved effective

A wide range of phosphonium based RTILs have been explored for use in the Heck reaction.[46] Of particular note was the use of salts such as [P6,6,6,14][Cl] in the Heck coupling of deactivated and sterically demanding aryl halides (Scheme 7).[47]-[50] Even with deactivated aryl halides these reactions required mild conditions and short reaction duration (50 ºC and 2 h). The reaction requires only 50 °C within 2 h. The solvent and catalyst could be reused. Furthermore, the phosphonium RTIL anion influenced reaction outcome chloride and decanoate anions giving superior outcomes than

The phosphine free Pd(OAC)2 / or PdCl2 mediated Heck coupling has been conducted in [P6,6,6,14][Br], which also

The imidazolium RTILs gave low coupling yield in the absence of phosphine ligands. Addition of Ph3P to [bmim][PF6] saw a significant rise in *E*-ethyl cinnamate yield to 99%, and this system could be re-used six times with no observable loss in catalyst activity. Pure product was obtained directly via hexane extraction. This approach was also suitable for coupling of the less reactive 4-bromoanisole where the effect of group 15 ligands was also explored and showed enhanced yields relative to the classical approach. The RTILs [*N*-C6H13Py][Cl] and [bmim][BF4] allowed the facile coupling of benzoic anhydride (as the aryl moiety source) and butyl acrylate giving *trans-*butyl cinnamate in 90-95%. This coupling was conducted at 160 °C with [*N*-C6H13Py][Cl] and PdCl2, and 200 ºC with [bmim][BF4] and Pd(OAc)2 and

The imidazolium RTILs gave low coupling yield in the absence of phosphine ligands. Addition of Ph3P to [bmim][PF6] saw a significant rise in *E*-ethyl cinnamate yield to 99%, and this system could be re-used six times with no observable loss in catalyst activity. Pure product was obtained directly via hexane extraction. This approach was also suitable for coupling of the less reactive 4-bromoanisole where the effect of group 15 ligands was also explored and showed enhanced yields relative to the classical approach. The RTILs [*N*-C6H13Py][Cl] and [bmim][BF4] allowed the facile coupling of benzoic anhydride (as the aryl moiety source) and butyl acrylate giving *trans-*butyl cinnamate in 90-95%. This coupling was conducted at 160 °C with [*N*-C6H13Py][Cl] and PdCl2, and 200 ºC with [bmim][BF4] and Pd(OAc)2 and P(*o*-tol)3.[33] Xiao *et al* noted that [bmim][BF4] promoted the ionic pathway in the arylation of electron-rich olefins

Sheme 1.Reagents and conditions: 2 mol % Pd(OAc)2, a RTIL (see Table 1 for detail), Et3N or NaHCO3, 40-100 ºC, 24-72 h.

Sheme 1.Reagents and conditions: 2 mol % Pd(OAc)2, a RTIL (see Table 1 for detail), Et3N or NaHCO3, 40-100 ºC, 24-72 h.

[*N*-C6H13Py]Cl Et3N 40 24 99 [*N*-C6H13Py]Cl NaHCO3 40 24 98 [*N*-C6H13Py][PF6] NaHCO3 80 72 42 [*N*-C6H13Py][BF4] NaHCO3 80 72 99 [*N*-C6H13Py]Cl NaHCO3 40 24 82 [*N*-C6H13Py]Cl NaHCO3 100 24 99 [pmim]Cl Et3N 80 72 10 [pmim]Cl NaHCO3 100 24 19 [pmim]Cl NaHCO3 40 24 77 Table 1. Heck coupling of iodobenzene and ethyl acrylate to give *E*-ethyl cinnamate in *N*-hexylpyridinium and methylimidazolium

[*N*-C6H13Py]Cl Et3N 40 24 99 [*N*-C6H13Py]Cl NaHCO3 40 24 98 [*N*-C6H13Py][PF6] NaHCO3 80 72 42 [*N*-C6H13Py][BF4] NaHCO3 80 72 99 [*N*-C6H13Py]Cl NaHCO3 40 24 82 [*N*-C6H13Py]Cl NaHCO3 100 24 99 [pmim]Cl Et3N 80 72 10 [pmim]Cl NaHCO3 100 24 19 [pmim]Cl NaHCO3 40 24 77 Table 1. Heck coupling of iodobenzene and ethyl acrylate to give *E*-ethyl cinnamate in *N*-hexylpyridinium and methylimidazolium

**RTIL Base Temp. °C Time (h) Yield %** 

**RTIL Base Temp. °C Time (h) Yield %** 


RTILs and 2 mol% Pd(OAc)2.

RTILs and 2 mol% Pd(OAc)2.

**RTIL Base Temp. °C Time (h) Yield %**  a reaction with ethyl acrylate, b reaction with butyl acrylate. a reaction with ethyl acrylate, b reaction with butyl acrylate.

P(*o*-tol)3.

[*N*-C6H13Py][PF6] NaHCO3 80 72 42 [*N*-C6H13Py][BF4] NaHCO3 80 72 99 [*N*-C6H13Py]Cl NaHCO3 40 24 82 [*N*-C6H13Py]Cl NaHCO3 100 24 99 [pmim]Cl Et3N 80 72 10

saw a significant rise in *E*-ethyl cinnamate yield to 99%, and this system could be re-used six times with no observable

This coupling was conducted at 160 °C with [*N*-C6H13Py][Cl] and PdCl2, and 200 ºC with [bmim][BF4] and Pd(OAc)2 and

4-bromobenzaldehydeb 100 3

good yields of the Heck coupling product (Scheme 2). Product isolation was by extraction allowing direct reuse of the

Arene diazonium salts in RTILs have proved to be viable alternatives to aryl bromides and iodides in Pd-mediated couplings.[36],[37] In [bmim][PF6], arene diazonium BF4 salts were readily coupled with acrylonitrile, but vinyl ethers and esters were less reactive requiring more forcing conditions of higher temperature and longer reaction duration (Scheme

[bmim][BF4] iodobenzenea 90 35

Table 2. Selected results for Heck reaction between the listed arylhalides and ethyl acrylate or butyl acrylate in [Bmim]Br and

RTILs and 2 mol% Pd(OAc)2.

**Sheme 1.** Reagents and conditions: 2 mol % Pd(OAc)2, a RTIL (see Table 1 for detail), Et3N or NaHCO3, 40-100 °C,

[*N*-C6H13Py]Cl Et3N 40 24 99 [*N*-C6H13Py]Cl NaHCO3 40 24 98 [*N*-C6H13Py][PF6] NaHCO3 80 72 42 [*N*-C6H13Py][BF4] NaHCO3 80 72 99 [*N*-C6H13Py]Cl NaHCO3 40 24 82 [*N*-C6H13Py]Cl NaHCO3 100 24 99 [pmim]Cl Et3N 80 72 10 [pmim]Cl NaHCO3 100 24 19 [pmim]Cl NaHCO3 40 24 77

RTIL Base Temp. °C Time (h) Yield %

affording high -regioselectivity (Table 2).[34]

**Table 1.** Heck coupling of iodobenzene and ethyl acrylate to give *E*-ethyl cinnamate in *N*-hexylpyridinium and

The imidazolium RTILs gave low coupling yield in the absence of phosphine ligands. Addition of Ph3P to [bmim][PF6] saw a significant rise in *E*-ethyl cinnamate yield to 99%, and this system could be re-used six times with no observable loss in catalyst activity. Pure product was obtained directly via hexane extraction. This approach was also suitable for coupling of the less reactive 4-bromoanisole where the effect of group 15 ligands was also explored and showed enhanced yields relative to the classical approach. The RTILs [*N*-C6H13Py][Cl] and [bmim][BF4] allowed the facile coupling of benzoic anhydride (as the aryl moiety source) and butyl acrylate giving *trans-*butyl cinnamate in 90-95%. This coupling was conducted at 160 °C with [*N*-C6H13Py][Cl] and PdCl2, and 200 °C with [bmim][BF4] and Pd(OAc)2 and P(*o*-tol)3.[33] Xiao *et al* noted that [bmim][BF4] promoted the ionic pathway in the arylation of electron-rich

a reaction with ethyl acrylate, b reaction with butyl acrylate.

Sheme 2.Reagents and conditions: 3 mol % Pd/C (10%) / [bmim][PF6], Et3N, .

RTIL and catalyst without loss of coupling efficiency.[35]

Yokoyama showed that heating an aryl substrate, olefin and 3 mol% of 10% Pd/C dispersed in [bmim][PF6] afforded good yields of the Heck coupling product (Scheme 2). Product isolation was by extraction allowing direct reuse of the RTIL and catalyst without loss of

P(*o*-tol)3.

methylimidazolium RTILs and 2 mol% Pd(OAc)2.

24-72 h.

32 Ionic Liquids - Current State of the Art

[Bmim]BF4.

olefins affording high α-regioselectivity (Table 2).[34]

3).[38]

coupling efficiency.[35]

[*N*-C6H13Py]Cl Et3N 40 24 99 [*N*-C6H13Py]Cl NaHCO3 40 24 98 Yokoyama showed that heating an aryl substrate, olefin and 3 mol% of 10% Pd/C dispersed in [bmim][PF6] afforded good yields of the Heck coupling product (Scheme 2). Product isolation was by extraction allowing direct reuse of the a reaction with ethyl acrylate, b reaction with butyl acrylate. Yokoyama showed that heating an aryl substrate, olefin and 3 mol% of 10% Pd/C dispersed in [bmim][PF6] afforded good yields of the Heck coupling product (Scheme 2). Product isolation was by extraction allowing direct reuse of the **Table 2.** Selected results for Heck reaction between the listed arylhalides and ethyl acrylate or butyl acrylate in [Bmim]Br and [Bmim]BF4.

RTIL and catalyst without loss of coupling efficiency.[35]

RTIL and catalyst without loss of coupling efficiency.[35]

Sheme 2.Reagents and conditions: 3 mol % Pd/C (10%) / [bmim][PF6], Et3N, .

benzofurans (Scheme 5). The isolated yields varied from modest to good.[40]

Sheme 5.Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 ºC, 24 h.

Sheme 6.Reagents and conditions: 2 mol % Pd-catalyst, [BMIM]BF4, 60 ºC, 24 h.

Sheme 7.Reagents and conditions: [P6,6,6,14][Cl], Pd(OAc)2, 100 ºC, 18-24 h.

Sheme 8.Reagents and conditions: [P6,6,6,14][Br], Pd(OAc)2, 100 ºC, 124 h.

represented the first report of a Pd-couling reaction in a RTIL (Scheme 8).[46]

recyclable (five cycles with no loss of activity) Heck coupling catalysts.[4][1]-[4][5]

[pmim]Cl NaHCO3 100 24 19 Sheme 2.Reagents and conditions: 3 mol % Pd/C (10%) / [bmim][PF6], Et3N, . **Sheme 2.** Reagents and conditions: 3 mol % Pd/C (10%) / [bmim][PF6], Et3N, Δ.

3).[38]

[pmim]Cl NaHCO3 40 24 77 Table 1. Heck coupling of iodobenzene and ethyl acrylate to give *E*-ethyl cinnamate in *N*-hexylpyridinium and methylimidazolium The imidazolium RTILs gave low coupling yield in the absence of phosphine ligands. Addition of Ph3P to [bmim][PF6] Arene diazonium salts in RTILs have proved to be viable alternatives to aryl bromides and iodides in Pd-mediated couplings.[36],[37] In [bmim][PF6], arene diazonium BF4 salts were readily coupled with acrylonitrile, but vinyl ethers and esters were less reactive requiring more forcing conditions of higher temperature and longer reaction duration (Scheme 3).[38] Arene diazonium salts in RTILs have proved to be viable alternatives to aryl bromides and iodides in Pd-mediated couplings.[36, 37] In [bmim][PF6], arene diazonium BF4 salts were readily coupled with acrylonitrile, but vinyl ethers and esters were less reactive requiring more forcing conditions of higher temperature and longer reaction duration (Scheme 3).[38] Arene diazonium salts in RTILs have proved to be viable alternatives to aryl bromides and iodides in Pd-mediated couplings.[36],[37] In [bmim][PF6], arene diazonium BF4 salts were readily coupled with acrylonitrile, but vinyl ethers and esters were less reactive requiring more forcing conditions of higher temperature and longer reaction duration (Scheme

[33] Xiao *et al* noted that [bmim][BF4] promoted the ionic pathway in the arylation of electron-rich olefins **Sheme 3.** Reagents and conditions: 2 mol % Pd(OAc)2, [bmim][PF6] at 50 °C, 2-4 h. Sheme 3.Reagents and conditions: 2 mol % Pd(OAc)2, [bmim][PF6] at 50 °C, 2-4 h.

**ILs Aryl halide Temp. °C Halide conversion %**  [bmim][Br] iodobenzenea 90 94 4-bromobenzaldehydeb 100 71 The Pd(OAc)2 mediated intramolecular Heck reaction of *o*-iodoarylallyl ethers present an attractive route to benzofurans, but typically requires extended reaction times in traditional solvents (80 °C, 2 days).[39] However, in [bmim][BF4] treatment of *o*-iodobenzyl allyl ether with 5 mol % PdCl2, 1.5 eq. (n-Bu)3N and 1 eq. NH4OOCH at 60 °C for 24 h gave 3-methyl‐ benzofuran in a 71% yield (Scheme 4).[40] The Pd(OAc)2 mediated intramolecular Heck reaction of *o*-iodoarylallyl ethers present an attractive route to benzofurans, but typically requires extended reaction times in traditional solvents (80 ºC, 2 days).[39] However, in [bmim][BF4] treatment of *o*-iodobenzyl allyl ether with 5 mol % PdCl2, 1.5 eq. (n-Bu)3N and 1 eq. NH4OOCH at 60 °C for 24 h gave 3 methylbenzofuran in a 71% yield (Scheme 4).[40]

**2.2. Phosphonium RTILs** 

[47]

with BF4 and PF6.

Yokoyama showed that heating an aryl substrate, olefin and 3 mol% of 10% Pd/C dispersed in [bmim][PF6] afforded Sheme 4.Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 ºC, 24 h. **Sheme 4.** Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 °C, 24 h.

The use of more substituted *o*-iodoaryl allyl ethers using the above approach allowed rapid access to 3-substituted benzofurans (Scheme 5). The isolated yields varied from modest to good.[40] Figure 6. Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 ºC, 24 h. The use of more substituted *o*-iodoaryl allyl ethers using the above approach allowed rapid access to 3-substituted methylbenzofuran in a 71% yield (Scheme 4).[40]

methylbenzofuran in a 71% yield (Scheme 4).[40]

methylbenzofuran in a 71% yield (Scheme 4).[40]

Figure 5. Reagents and conditions: 2 mol % Pd(OAc)2, [bmim][PF6] at 50 °C, 2-4 h.

Figure 5. Reagents and conditions: 2 mol % Pd(OAc)2, [bmim][PF6] at 50 °C, 2-4 h.

Figure 5. Reagents and conditions: 2 mol % Pd(OAc)2, [bmim][PF6] at 50 °C, 2-4 h.

benzofurans (Scheme 5). The isolated yields varied from modest to good.[40]

but typically requires extended reaction times in traditional solvents (80 ºC, 2 days).[39] However, in [bmim][BF4] treatment of *o*-iodobenzyl allyl ether with 5 mol % PdCl2, 1.5 eq. (n-Bu)3N and 1 eq. NH4OOCH at 60 °C for 24 h gave 3-

The Pd(OAc)2 mediated intramolecular Heck reaction of *o*-iodoarylallyl ethers present an attractive route to benzofurans,

treatment of *o*-iodobenzyl allyl ether with 5 mol % PdCl2, 1.5 eq. (n-Bu)3N and 1 eq. NH4OOCH at 60 °C for 24 h gave 3-

Specialty highly recyclable Pd-complexes, such as Alper's Pd(II)-bisimidazole (Scheme 6), have proved effective

The Pd(OAc)2 mediated intramolecular Heck reaction of *o*-iodoarylallyl ethers present an attractive route to benzofurans, but typically requires extended reaction times in traditional solvents (80 ºC, 2 days).[39] However, in [bmim][BF4] treatment of *o*-iodobenzyl allyl ether with 5 mol % PdCl2, 1.5 eq. (n-Bu)3N and 1 eq. NH4OOCH at 60 °C for 24 h gave 3-

phosphonium RTIL anion influenced reaction outcome chloride and decanoate anions giving superior outcomes than

Figure 7. Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 ºC, 24 h. **Sheme 5.** Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 °C, 24 h.

Specialty highly recyclable Pd-complexes, such as Alper's Pd(II)-bisimidazole (Scheme 6), have proved effective recyclable (five cycles with no loss of activity) Heck coupling catalysts.[4][1]-[4][5] Specialty highly recyclable Pd-complexes, such as Alper's Pd(II)-bisimidazole (Scheme 6), have proved effective recyclable (five cycles with no loss of activity) Heck coupling catalysts. [4][1][4][5] Figure 7. Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 ºC, 24 h. Specialty highly recyclable Pd-complexes, such as Alper's Pd(II)-bisimidazole (Scheme 6), have proved effective Figure 7. Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 ºC, 24 h.

recyclable (five cycles with no loss of activity) Heck coupling catalysts.[4][1]-[4][5]

Figure 8. Reagents and conditions: 2 mol % Pd-catalyst, [BMIM]BF4, 60 ºC, 24 h.

recyclable (five cycles with no loss of activity) Heck coupling catalysts.[4][1]-[4][5]

Figure 8. Reagents and conditions: 2 mol % Pd-catalyst, [BMIM]BF4, 60 ºC, 24 h. Figure 8. Reagents and conditions: 2 mol % Pd-catalyst, [BMIM]BF4, 60 ºC, 24 h. **Sheme 6.** Reagents and conditions: 2 mol % Pd-catalyst, [BMIM]BF4, 60 °C, 24 h.

#### **2.2. Phosphonium RTILs 2.2. Phosphonium RTILs**

**2.2. Phosphonium RTILs**  A wide range of phosphonium based RTILs have been explored for use in the Heck reaction.[46] Of particular note was the use of salts such as [P6,6,6,14][Cl] in the Heck coupling of deactivated and sterically demanding aryl halides (Scheme 7).[47]-[50] Even with deactivated aryl halides these reactions required mild conditions and short reaction duration (50 ºC and 2 h). The reaction requires only 50 °C within 2 h. The solvent and catalyst could be reused. Furthermore, the A wide range of phosphonium based RTILs have been explored for use in the Heck reaction.[46] Of particular note was the use of salts such as [P6,6,6,14][Cl] in the Heck coupling of deactivated and sterically demanding aryl halides (Scheme 7).[47]-[50] Even with deactivated aryl halides these reactions required mild conditions and short reaction duration (50 ºC and 2 h). The reaction requires only 50 °C within 2 h. The solvent and catalyst could be reused. Furthermore, the phosphonium RTIL anion influenced reaction outcome chloride and decanoate anions giving superior outcomes than with BF4 and PF6. [47] A wide range of phosphonium based RTILs have been explored for use in the Heck reaction. [46] Of particular note was the use of salts such as [P6,6,6,14][Cl] in the Heck coupling of deactivated and sterically demanding aryl halides (Scheme 7).[47-50] Even with deactivated aryl halides these reactions required mild conditions and short reaction duration (50 °C and 2 h). The reaction requires only 50 °C within 2 h. The solvent and catalyst could be reused. Furthermore, the phosphonium RTIL anion influenced reaction outcome chloride and decanoate anions giving superior outcomes than with BF4 and PF6.[47] **2.2. Phosphonium RTILs**  A wide range of phosphonium based RTILs have been explored for use in the Heck reaction.[46] Of particular note was the use of salts such as [P6,6,6,14][Cl] in the Heck coupling of deactivated and sterically demanding aryl halides (Scheme 7).[47]-[50] Even with deactivated aryl halides these reactions required mild conditions and short reaction duration (50 ºC and 2 h). The reaction requires only 50 °C within 2 h. The solvent and catalyst could be reused. Furthermore, the phosphonium RTIL anion influenced reaction outcome chloride and decanoate anions giving superior outcomes than

[47]

[47]

represented the first report of a Pd-couling reaction in a RTIL (Scheme 8).[46] Figure 9. Reagents and conditions: [P6,6,6,14][Cl], Pd(OAc)2, 100 ºC, 18-24 h. **Sheme 7.** Reagents and conditions: [P6,6,6,14][Cl], Pd(OAc)2, 100 °C, 18-24 h.

with BF4 and PF6.

Figure 9. Reagents and conditions: [P6,6,6,14][Cl], Pd(OAc)2, 100 ºC, 18-24 h. The phosphine free Pd(OAC)2 / or PdCl2 mediated Heck coupling has been conducted in [P6,6,6,14][Br], which also The phosphine free Pd(OAC)2 / or PdCl2 mediated Heck coupling has been conducted in [P6,6,6,14][Br], which also represented the first report of a Pd-couling reaction in a RTIL (Scheme 8).[46] The phosphine free Pd(OAC)2 / or PdCl2 mediated Heck coupling has been conducted in [P6,6,6,14][Br], which also represented the first report of a Pd-couling reaction in a RTIL (Scheme 8).[46]

Figure 10. Reagents and conditions: [P6,6,6,14][Br], Pd(OAc)2, 100 ºC, 124 h.

Figure 10. Reagents and conditions: [P6,6,6,14][Br], Pd(OAc)2, 100 ºC, 124 h.

represented the first report of a Pd-couling reaction in a RTIL (Scheme 8).[46]

The phosphine free Pd(OAC)2 / or PdCl2 mediated Heck coupling has been conducted in [P6,6,6,14][Br], which also

Figure 10. Reagents and conditions: [P6,6,6,14][Br], Pd(OAc)2, 100 ºC, 124 h.

Figure 9. Reagents and conditions: [P6,6,6,14][Cl], Pd(OAc)2, 100 ºC, 18-24 h.

represented the first report of a Pd-couling reaction in a RTIL (Scheme 8).[46]

Figure 5. Reagents and conditions: 2 mol % Pd(OAc)2, [bmim][PF6] at 50 °C, 2-4 h.

Figure 6. Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 ºC, 24 h.

Figure 7. Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 ºC, 24 h.

Figure 8. Reagents and conditions: 2 mol % Pd-catalyst, [BMIM]BF4, 60 ºC, 24 h.

recyclable (five cycles with no loss of activity) Heck coupling catalysts.[4][1]-[4][5]

benzofurans (Scheme 5). The isolated yields varied from modest to good.[40]

methylbenzofuran in a 71% yield (Scheme 4).[40]

The Pd(OAc)2 mediated intramolecular Heck reaction of *o*-iodoarylallyl ethers present an attractive route to benzofurans, but typically requires extended reaction times in traditional solvents (80 ºC, 2 days).[39] However, in [bmim][BF4] treatment of *o*-iodobenzyl allyl ether with 5 mol % PdCl2, 1.5 eq. (n-Bu)3N and 1 eq. NH4OOCH at 60 °C for 24 h gave 3-

The use of more substituted *o*-iodoaryl allyl ethers using the above approach allowed rapid access to 3-substituted

Specialty highly recyclable Pd-complexes, such as Alper's Pd(II)-bisimidazole (Scheme 6), have proved effective

A wide range of phosphonium based RTILs have been explored for use in the Heck reaction.[46] Of particular note was the use of salts such as [P6,6,6,14][Cl] in the Heck coupling of deactivated and sterically demanding aryl halides (Scheme 7).[47]-[50] Even with deactivated aryl halides these reactions required mild conditions and short reaction duration (50 ºC and 2 h). The reaction requires only 50 °C within 2 h. The solvent and catalyst could be reused. Furthermore, the phosphonium RTIL anion influenced reaction outcome chloride and decanoate anions giving superior outcomes than

proposed that the RTIL phosphonium salt stabilised the Pd(0) species obtained by *in situ* reduction of the Pd(II) catalyst

diarylacrylates. This coupling was accomplished in good yield and regioselectivity in molten n-Bu4NOAc/n-Bu4NBr with

The Pd-benzothiazole carbene complex has been successfully used as the Pd-source (1.5 mol%), and easily recycled, in the coupling of both electron rich and electron deficient *trans*-cinnamates in [Bu4N][Br] at 130 ºC with added sodium formate and NaHCO3 (Scheme 12).[54],[55] The best yields were observed with NaOH and DBU and in these instances the

The Pd-benzothiazole carbene complex has been successfully used as the Pd-source (1.5 mol%), and easily recycled, in the coupling of both electron rich and electron deficient *trans*-cinnamates in [Bu4N][Br] at 130 ºC with added sodium formate and NaHCO3 (Scheme 12).[54],[55] The best yields were observed with NaOH and DBU and in these instances the

Motevalli's *N*-(diphenylphosphino)triethylammonium chloride (**IL1**) and *N*-(diphenylphosphino)tributylammonium chloride (**IL2**), have been used successfully in Heck couplings of iodobenzene and styrene (Figure 3 and Table 3).[56]

Motevalli's *N*-(diphenylphosphino)triethylammonium chloride (**IL1**) and *N*-(diphenylphosphino)tributylammonium chloride (**IL2**), have been used successfully in Heck couplings of iodobenzene and styrene (Figure 3 and Table 3).[56]

Figure 10. Reagents and conditions: [P6,6,6,14][Br], Pd(OAc)2, 100 ºC, 124 h. **Sheme 8.** Reagents and conditions: [P6,6,6,14][Br], Pd(OAc)2, 100 °C, 124 h.

**2.2. Phosphonium RTILs** 

[47]

with BF4 and PF6.

Specialty highly recyclable Pd-complexes, such as Alper's Pd(II)-bisimidazole (Scheme 6), have proved effective Specialty highly recyclable Pd-complexes, such as Alper's Pd(II)-bisimidazole (Scheme 6), have proved effective It was noted with Pd(OAc)2, that the addition of 1.5 eq. of NaOAc, improved the coupling rate, but decreased selectivity with 5% of the (*Z*)-isomer detected under these conditions. Also of note with this reaction sequence was the slow precipitation of Pd-clusters on use of PdCl2, but not with Pd(OAc)2. With Pd(OAc)2 the catalyst remained soluble and viable, able to catalyse subsequent couplings on removal of the product from the previous catalytic cycle. It was proposed that the RTIL phosphonium salt stabilised the Pd(0) species obtained by *in situ* reduction of the Pd(II) catalyst precursors. This ligand free approach has attracted considerable interest and has purification benefits on reaction scale up.[51] It was noted with Pd(OAc)2, that the addition of 1.5 eq. of NaOAc, improved the coupling rate, but decreased selectivity with 5% of the (*Z*)-isomer detected under these conditions. Also of note with this reaction sequence was the slow precipitation of Pd-clusters on use of PdCl2, but not with Pd(OAc)2. With Pd(OAc)2 the catalyst remained soluble and viable, able to catalyse subsequent couplings on removal of the product from the previous catalytic cycle. It was It was noted with Pd(OAc)2, that the addition of 1.5 eq. of NaOAc, improved the coupling rate, but decreased selectivity with 5% of the (*Z*)-isomer detected under these conditions. Also of note with this reaction sequence was the slow precipitation of Pd-clusters on use of PdCl2, but not with Pd(OAc)2. With Pd(OAc)2 the catalyst remained soluble and viable, able to catalyse subsequent couplings on removal of the product from the previous catalytic cycle. It was

#### Specialty highly recyclable Pd-complexes, such as Alper's Pd(II)-bisimidazole (Scheme 6), have proved effective **2.3. Ammonium RTILs** precursors. This ligand free approach has attracted considerable interest and has purification benefits on reaction scale up.[51] proposed that the RTIL phosphonium salt stabilised the Pd(0) species obtained by *in situ* reduction of the Pd(II) catalyst precursors. This ligand free approach has attracted considerable interest and has purification benefits on reaction scale

The use of more substituted *o*-iodoaryl allyl ethers using the above approach allowed rapid access to 3-substituted benzofurans (Scheme 5). The isolated yields varied from modest to

methylbenzofuran in a 71% yield (Scheme 4).[40]

methylbenzofuran in a 71% yield (Scheme 4).[40]

Specialty highly recyclable Pd-complexes, such as Alper's Pd(II)-bisimidazole (Scheme 6), have proved effective recyclable (five cycles with no loss of activity) Heck coupling catalysts.

**2.2. Phosphonium RTILs** 

A wide range of phosphonium based RTILs have been explored for use in the Heck reaction. [46] Of particular note was the use of salts such as [P6,6,6,14][Cl] in the Heck coupling of deactivated and sterically demanding aryl halides (Scheme 7).[47-50] Even with deactivated aryl halides these reactions required mild conditions and short reaction duration (50 °C and 2 h). The reaction requires only 50 °C within 2 h. The solvent and catalyst could be reused. Furthermore, the phosphonium RTIL anion influenced reaction outcome chloride and

**2.2. Phosphonium RTILs** 

**2.2. Phosphonium RTILs** 

[47]

[47]

[47]

The phosphine free Pd(OAC)2 / or PdCl2 mediated Heck coupling has been conducted in [P6,6,6,14][Br], which also represented the first report of a Pd-couling reaction in a RTIL

Figure 9. Reagents and conditions: [P6,6,6,14][Cl], Pd(OAc)2, 100 ºC, 18-24 h.

Figure 10. Reagents and conditions: [P6,6,6,14][Br], Pd(OAc)2, 100 ºC, 124 h.

Figure 10. Reagents and conditions: [P6,6,6,14][Br], Pd(OAc)2, 100 ºC, 124 h.

represented the first report of a Pd-couling reaction in a RTIL (Scheme 8).[46]

Figure 9. Reagents and conditions: [P6,6,6,14][Cl], Pd(OAc)2, 100 ºC, 18-24 h.

with BF4 and PF6.

decanoate anions giving superior outcomes than with BF4 and PF6.[47]

with BF4 and PF6.

with BF4 and PF6.

**Sheme 7.** Reagents and conditions: [P6,6,6,14][Cl], Pd(OAc)2, 100 °C, 18-24 h.

**Sheme 6.** Reagents and conditions: 2 mol % Pd-catalyst, [BMIM]BF4, 60 °C, 24 h.

**Sheme 5.** Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 °C, 24 h.

methylbenzofuran in a 71% yield (Scheme 4).[40]

Figure 5. Reagents and conditions: 2 mol % Pd(OAc)2, [bmim][PF6] at 50 °C, 2-4 h.

Figure 5. Reagents and conditions: 2 mol % Pd(OAc)2, [bmim][PF6] at 50 °C, 2-4 h.

Figure 6. Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 ºC, 24 h.

Figure 7. Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 ºC, 24 h.

Figure 8. Reagents and conditions: 2 mol % Pd-catalyst, [BMIM]BF4, 60 ºC, 24 h.

Figure 8. Reagents and conditions: 2 mol % Pd-catalyst, [BMIM]BF4, 60 ºC, 24 h.

recyclable (five cycles with no loss of activity) Heck coupling catalysts.[4][1]-[4][5]

recyclable (five cycles with no loss of activity) Heck coupling catalysts.[4][1]-[4][5]

Figure 7. Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 ºC, 24 h.

benzofurans (Scheme 5). The isolated yields varied from modest to good.[40]

benzofurans (Scheme 5). The isolated yields varied from modest to good.[40]

Figure 6. Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 ºC, 24 h.

Figure 5. Reagents and conditions: 2 mol % Pd(OAc)2, [bmim][PF6] at 50 °C, 2-4 h.

Figure 6. Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 ºC, 24 h.

Figure 7. Reagents and conditions: 5% PdCl2, (n-Bu)3N, [bmim][BF4], 60 ºC, 24 h.

Figure 8. Reagents and conditions: 2 mol % Pd-catalyst, [BMIM]BF4, 60 ºC, 24 h.

Figure 9. Reagents and conditions: [P6,6,6,14][Cl], Pd(OAc)2, 100 ºC, 18-24 h.

represented the first report of a Pd-couling reaction in a RTIL (Scheme 8).[46]

Figure 10. Reagents and conditions: [P6,6,6,14][Br], Pd(OAc)2, 100 ºC, 124 h.

represented the first report of a Pd-couling reaction in a RTIL (Scheme 8).[46]

recyclable (five cycles with no loss of activity) Heck coupling catalysts.[4][1]-[4][5]

benzofurans (Scheme 5). The isolated yields varied from modest to good.[40]

The Pd(OAc)2 mediated intramolecular Heck reaction of *o*-iodoarylallyl ethers present an attractive route to benzofurans, but typically requires extended reaction times in traditional solvents (80 ºC, 2 days).[39] However, in [bmim][BF4] treatment of *o*-iodobenzyl allyl ether with 5 mol % PdCl2, 1.5 eq. (n-Bu)3N and 1 eq. NH4OOCH at 60 °C for 24 h gave 3-

The Pd(OAc)2 mediated intramolecular Heck reaction of *o*-iodoarylallyl ethers present an attractive route to benzofurans, but typically requires extended reaction times in traditional solvents (80 ºC, 2 days).[39] However, in [bmim][BF4] treatment of *o*-iodobenzyl allyl ether with 5 mol % PdCl2, 1.5 eq. (n-Bu)3N and 1 eq. NH4OOCH at 60 °C for 24 h gave 3-

The use of more substituted *o*-iodoaryl allyl ethers using the above approach allowed rapid access to 3-substituted

The use of more substituted *o*-iodoaryl allyl ethers using the above approach allowed rapid access to 3-substituted

A wide range of phosphonium based RTILs have been explored for use in the Heck reaction.[46] Of particular note was the use of salts such as [P6,6,6,14][Cl] in the Heck coupling of deactivated and sterically demanding aryl halides (Scheme 7).[47]-[50] Even with deactivated aryl halides these reactions required mild conditions and short reaction duration (50 ºC

7).[47]-[50] Even with deactivated aryl halides these reactions required mild conditions and short reaction duration (50 ºC

The phosphine free Pd(OAC)2 / or PdCl2 mediated Heck coupling has been conducted in [P6,6,6,14][Br], which also

The Pd(OAc)2 mediated intramolecular Heck reaction of *o*-iodoarylallyl ethers present an attractive route to benzofurans, but typically requires extended reaction times in traditional solvents (80 ºC, 2 days).[39] However, in [bmim][BF4] treatment of *o*-iodobenzyl allyl ether with 5 mol % PdCl2, 1.5 eq. (n-Bu)3N and 1 eq. NH4OOCH at 60 °C for 24 h gave 3-

The phosphine free Pd(OAC)2 / or PdCl2 mediated Heck coupling has been conducted in [P6,6,6,14][Br], which also

good.[40]

34 Ionic Liquids - Current State of the Art

[4][1][4][5]

**2.2. Phosphonium RTILs**

(Scheme 8).[46]

Tetraammonium salts are the archetypal ammonium based RTILs used in the Heck coupling, with the simplest being the tetrabutylammonium salts ([Bu4N][X]). Coupling of iodobenzene with arylacrylates gave an expedient synthesis of 3,3-diarylacrylates. This coupling was accomplished in good yield and regioselectivity in molten n-Bu4NOAc/n-Bu4NBr with Pd(OAc)2 (Scheme 9).[52] **2.3. Ammonium RTILs**  Tetraammonium salts are the archetypal ammonium based RTILs used in the Heck coupling, with the simplest being the tetrabutylammonium salts ([Bu4N][X]). Coupling of iodobenzene with arylacrylates gave an expedient synthesis of 3,3 diarylacrylates. This coupling was accomplished in good yield and regioselectivity in molten n-Bu4NOAc/n-Bu4NBr with up.[51] **2.3. Ammonium RTILs**  Tetraammonium salts are the archetypal ammonium based RTILs used in the Heck coupling, with the simplest being the tetrabutylammonium salts ([Bu4N][X]). Coupling of iodobenzene with arylacrylates gave an expedient synthesis of 3,3-

the use of salts such as [P6,6,6,14][Cl] in the Heck coupling of deactivated and sterically demanding aryl halides (Scheme and 2 h). The reaction requires only 50 °C within 2 h. The solvent and catalyst could be reused. Furthermore, the phosphonium RTIL anion influenced reaction outcome chloride and decanoate anions giving superior outcomes than the use of salts such as [P6,6,6,14][Cl] in the Heck coupling of deactivated and sterically demanding aryl halides (Scheme Figure 11. Reagents and conditions: Pd(OAc)2, *n*-Bu4NOAc/*n*-Bu4NBr, 100 ºC. **Sheme 9.** Reagents and conditions: Pd(OAc)2, *n*-Bu4NOAc/*n*-Bu4NBr, 100 °C.

Pd(OAc)2 (Scheme 9).[52]

7).[47]-[50] Even with deactivated aryl halides these reactions required mild conditions and short reaction duration (50 ºC and 2 h). The reaction requires only 50 °C within 2 h. The solvent and catalyst could be reused. Furthermore, the phosphonium RTIL anion influenced reaction outcome chloride and decanoate anions giving superior outcomes than and 2 h). The reaction requires only 50 °C within 2 h. The solvent and catalyst could be reused. Furthermore, the phosphonium RTIL anion influenced reaction outcome chloride and decanoate anions giving superior outcomes than Others have noted the increased stability of the Pd-catalytic species in RTILs and have exploited this in the PdCl2 mediated synthesis of β-arylcarbonyl compounds from allylic alcohols in [Bu4N]Br, affording (Scheme 10).[53] Extension of this simple procedure afforded a one-step synthesis of the nonsteroidal antiinflammatory drug (nabumethone), (Scheme 11) and allowed catalyst reuse.[53] Others have noted the increased stability of the Pd-catalytic species in RTILs and have exploited this in the PdCl2 mediated synthesis of β-arylcarbonyl compounds from allylic alcohols in [Bu4N]Br, affording (Scheme 10).[53] Extension of this simple procedure afforded a one-step synthesis of the nonsteroidal antiinflammatory drug (nabumethone), (Scheme 11) and allowed catalyst reuse.[53] Figure 11. Reagents and conditions: Pd(OAc)2, *n*-Bu4NOAc/*n*-Bu4NBr, 100 ºC. Others have noted the increased stability of the Pd-catalytic species in RTILs and have exploited this in the PdCl2 mediated synthesis of β-arylcarbonyl compounds from allylic alcohols in [Bu4N]Br, affording (Scheme 10).[53] Extension of this simple procedure afforded a one-step synthesis of the nonsteroidal antiinflammatory drug (nabumethone),

(Scheme 11) and allowed catalyst reuse.[53]

Figure 13. Reagents and conditions: PdCl2, NaHCO3 (1.2 equiv.), Bu4NBr, 120 ºC, 24 h.

Figure 13. Reagents and conditions: PdCl2, NaHCO3 (1.2 equiv.), Bu4NBr, 120 ºC, 24 h.

Figure 14. Reagents and conditions: [Bu4N]Br, NaOAc, NaHCO3, 130 ºC, Pd-cat.

Figure 14. Reagents and conditions: [Bu4N]Br, NaOAc, NaHCO3, 130 ºC, Pd-cat.

Figure 12. Reagents and conditions: PdCl2, NaHCO3, Bu4NBr, 120 ºC, 24 h. **Sheme 10.** Reagents and conditions: PdCl2, NaHCO3, Bu4NBr, 120 °C, 24 h.

reactions were complete in < 30 min.

reactions were complete in < 30 min.

up.[51]

up.[51]

**2.3. Ammonium RTILs** 

Pd(OAc)2 (Scheme 9).[52]

**2.3. Ammonium RTILs** 

Pd(OAc)2 (Scheme 9).[52]

Figure 12. Reagents and conditions: PdCl2, NaHCO3, Bu4NBr, 120 ºC, 24 h.

(Scheme 11) and allowed catalyst reuse.[53]

Figure 11. Reagents and conditions: Pd(OAc)2, *n*-Bu4NOAc/*n*-Bu4NBr, 100 ºC.

It was noted with Pd(OAc)2, that the addition of 1.5 eq. of NaOAc, improved the coupling rate, but decreased selectivity with 5% of the (*Z*)-isomer detected under these conditions. Also of note with this reaction sequence was the slow precipitation of Pd-clusters on use of PdCl2, but not with Pd(OAc)2. With Pd(OAc)2 the catalyst remained soluble and viable, able to catalyse subsequent couplings on removal of the product from the previous catalytic cycle. It was proposed that the RTIL phosphonium salt stabilised the Pd(0) species obtained by *in situ* reduction of the Pd(II) catalyst precursors. This ligand free approach has attracted considerable interest and has purification benefits on reaction scale

Tetraammonium salts are the archetypal ammonium based RTILs used in the Heck coupling, with the simplest being the tetrabutylammonium salts ([Bu4N][X]). Coupling of iodobenzene with arylacrylates gave an expedient synthesis of 3,3 diarylacrylates. This coupling was accomplished in good yield and regioselectivity in molten n-Bu4NOAc/n-Bu4NBr with

Others have noted the increased stability of the Pd-catalytic species in RTILs and have exploited this in the PdCl2 mediated synthesis of β-arylcarbonyl compounds from allylic alcohols in [Bu4N]Br, affording (Scheme 10).[53] Extension

formate and NaHCO3 (Scheme 12).[54],[55] The best yields were observed with NaOH and DBU and in these instances the

Motevalli's *N*-(diphenylphosphino)triethylammonium chloride (**IL1**) and *N*-(diphenylphosphino)tributylammonium chloride (**IL2**), have been used successfully in Heck couplings of iodobenzene and styrene (Figure 3 and Table 3).[56]

It was noted with Pd(OAc)2, that the addition of 1.5 eq. of NaOAc, improved the coupling rate, but decreased selectivity with 5% of the (*Z*)-isomer detected under these conditions. Also of note with this reaction sequence was the slow precipitation of Pd-clusters on use of PdCl2, but not with Pd(OAc)2. With Pd(OAc)2 the catalyst remained soluble and viable, able to catalyse subsequent couplings on removal of the product from the previous catalytic cycle. It was proposed that the RTIL phosphonium salt stabilised the Pd(0) species obtained by *in situ* reduction of the Pd(II) catalyst precursors. This ligand free approach has attracted considerable interest and has purification benefits on reaction scale

Tetraammonium salts are the archetypal ammonium based RTILs used in the Heck coupling, with the simplest being the tetrabutylammonium salts ([Bu4N][X]). Coupling of iodobenzene with arylacrylates gave an expedient synthesis of 3,3 diarylacrylates. This coupling was accomplished in good yield and regioselectivity in molten n-Bu4NOAc/n-Bu4NBr with

Others have noted the increased stability of the Pd-catalytic species in RTILs and have exploited this in the PdCl2 mediated synthesis of β-arylcarbonyl compounds from allylic alcohols in [Bu4N]Br, affording (Scheme 10).[53] Extension of this simple procedure afforded a one-step synthesis of the nonsteroidal antiinflammatory drug (nabumethone),

Figure 13. Reagents and conditions: PdCl2, NaHCO3 (1.2 equiv.), Bu4NBr, 120 ºC, 24 h. **Sheme 11.** Reagents and conditions: PdCl2, NaHCO3 (1.2 equiv.), Bu4NBr, 120 °C, 24 h. Figure 12. Reagents and conditions: PdCl2, NaHCO3, Bu4NBr, 120 ºC, 24 h.

The Pd-benzothiazole carbene complex has been successfully used as the Pd-source (1.5 mol%), and easily recycled, in the coupling of both electron rich and electron deficient *trans*-cinnamates in [Bu4N][Br] at 130 ºC with added sodium formate and NaHCO3 (Scheme 12).[54],[55] The best yields were observed with NaOH and DBU and in these instances the reactions were complete in < 30 min. The Pd-benzothiazole carbene complex has been successfully used as the Pd-source (1.5 mol %), and easily recycled, in the coupling of both electron rich and electron deficient *trans*cinnamates in [Bu4N][Br] at 130 °C with added sodium formate and NaHCO3 (Scheme 12).[54, 55] The best yields were observed with NaOH and DBU and in these instances the reactions were complete in < 30 min. Figure 13. Reagents and conditions: PdCl2, NaHCO3 (1.2 equiv.), Bu4NBr, 120 ºC, 24 h. The Pd-benzothiazole carbene complex has been successfully used as the Pd-source (1.5 mol%), and easily recycled, in the coupling of both electron rich and electron deficient *trans*-cinnamates in [Bu4N][Br] at 130 ºC with added sodium

Motevalli's *N*-(diphenylphosphino)triethylammonium chloride (**IL1**) and *N*-(diphenylphosphino)tributylammonium chloride (**IL2**), have been used successfully in Heck couplings of iodobenzene and styrene (Figure 3 and Table 3).[56] Figure 14. Reagents and conditions: [Bu4N]Br, NaOAc, NaHCO3, 130 ºC, Pd-cat. **Sheme 12.** Reagents and conditions: [Bu4N]Br, NaOAc, NaHCO3, 130 °C, Pd-cat.

reactions were complete in < 30 min.

Motevalli's *N*-(diphenylphosphino)triethylammonium chloride (**IL1**) and *N*-(diphenylphos‐ phino)tributylammonium chloride (**IL2**), have been used successfully in Heck couplings of iodobenzene and styrene (Figure 3 and Table 3).[56]

**Figure 3.** Structures of *N*-(diphenylphosphino)triethylammonium chloride (**IL1**) and *N*-(diphenylphosphino)tributy‐ lammonium chloride (**IL2**).

#### **2.4. Studies using imidazolium, pyridinium, phosphonium and ammonium RTILs**

The coupling of electron poor chloroarenes with mono and di-substituted olefins across a range of RTILs and Pd-sources has been examined.[57] The model system, resulting in the synthesis of stilbene from chlorobenzene and styrene was best conducted with simple, e.g. PdCl2, phospha-based Pd-sources (Scheme 13). RTILs examined included: imidazolium, ammonium and phosphonium salts. The tetraalkylammonium salts, in particular [Bu4N][Br], were superior permitting the coupling of chloroarenes in the presence of less active catalysts such as PdCl2 and Pd(Ph3P)4. Regardless of the conditions used, all imidazolium based RTILs gave poor results, e.g. 22 % for [bmim][BF4] and 13 % for [bmim][Br] whereas TBAB gave 72 % of the desired stilbene. With [bmim][BF4] there was clear evidence of the formation of Pd black.[57]

**Table 3.** Effect of different bases on Heck reaction of bromobenzene and styrene in *N*- (diphenylphosphino)triethylammonium chloride (**IL1**).

It was noted with Pd(OAc)2, that the addition of 1.5 eq. of NaOAc, improved the coupling rate, but decreased selectivity with 5% of the (*Z*)-isomer detected under these conditions. Also of note with this reaction sequence was the slow precipitation of Pd-clusters on use of PdCl2, but not with Pd(OAc)2. With Pd(OAc)2 the catalyst remained soluble and viable, able to catalyse subsequent couplings on removal of the product from the previous catalytic cycle. It was proposed that the RTIL phosphonium salt stabilised the Pd(0) species obtained by *in situ* reduction of the Pd(II) catalyst precursors. This ligand free approach has attracted considerable interest and has purification benefits on reaction scale

Tetraammonium salts are the archetypal ammonium based RTILs used in the Heck coupling, with the simplest being the tetrabutylammonium salts ([Bu4N][X]). Coupling of iodobenzene with arylacrylates gave an expedient synthesis of 3,3 diarylacrylates. This coupling was accomplished in good yield and regioselectivity in molten n-Bu4NOAc/n-Bu4NBr with

Others have noted the increased stability of the Pd-catalytic species in RTILs and have exploited this in the PdCl2 mediated synthesis of β-arylcarbonyl compounds from allylic alcohols in [Bu4N]Br, affording (Scheme 10).[53] Extension of this simple procedure afforded a one-step synthesis of the nonsteroidal antiinflammatory drug (nabumethone),

Motevalli's *N*-(diphenylphosphino)triethylammonium chloride (**IL1**) and *N*-(diphenylphosphino)tributylammonium chloride (**IL2**), have been used successfully in Heck couplings of iodobenzene and styrene (Figure 3 and Table 3).[56]

up.[51]

up.[51]

**2.3. Ammonium RTILs** 

Pd(OAc)2 (Scheme 9).[52]

**2.3. Ammonium RTILs** 

Pd(OAc)2 (Scheme 9).[52]

Figure 11. Reagents and conditions: Pd(OAc)2, *n*-Bu4NOAc/*n*-Bu4NBr, 100 ºC.

It was noted with Pd(OAc)2, that the addition of 1.5 eq. of NaOAc, improved the coupling rate, but decreased selectivity with 5% of the (*Z*)-isomer detected under these conditions. Also of note with this reaction sequence was the slow precipitation of Pd-clusters on use of PdCl2, but not with Pd(OAc)2. With Pd(OAc)2 the catalyst remained soluble and viable, able to catalyse subsequent couplings on removal of the product from the previous catalytic cycle. It was proposed that the RTIL phosphonium salt stabilised the Pd(0) species obtained by *in situ* reduction of the Pd(II) catalyst precursors. This ligand free approach has attracted considerable interest and has purification benefits on reaction scale

Tetraammonium salts are the archetypal ammonium based RTILs used in the Heck coupling, with the simplest being the tetrabutylammonium salts ([Bu4N][X]). Coupling of iodobenzene with arylacrylates gave an expedient synthesis of 3,3 diarylacrylates. This coupling was accomplished in good yield and regioselectivity in molten n-Bu4NOAc/n-Bu4NBr with

Others have noted the increased stability of the Pd-catalytic species in RTILs and have exploited this in the PdCl2 mediated synthesis of β-arylcarbonyl compounds from allylic alcohols in [Bu4N]Br, affording (Scheme 10).[53] Extension of this simple procedure afforded a one-step synthesis of the nonsteroidal antiinflammatory drug (nabumethone),

The Pd-benzothiazole carbene complex has been successfully used as the Pd-source (1.5 mol%), and easily recycled, in the coupling of both electron rich and electron deficient *trans*-cinnamates in [Bu4N][Br] at 130 ºC with added sodium formate and NaHCO3 (Scheme 12).[54],[55] The best yields were observed with NaOH and DBU and in these instances the

Motevalli's *N*-(diphenylphosphino)triethylammonium chloride (**IL1**) and *N*-(diphenylphosphino)tributylammonium chloride (**IL2**), have been used successfully in Heck couplings of iodobenzene and styrene (Figure 3 and Table 3).[56]

Figure 12. Reagents and conditions: PdCl2, NaHCO3, Bu4NBr, 120 ºC, 24 h.

The Pd-benzothiazole carbene complex has been successfully used as the Pd-source (1.5 mol %), and easily recycled, in the coupling of both electron rich and electron deficient *trans*cinnamates in [Bu4N][Br] at 130 °C with added sodium formate and NaHCO3 (Scheme 12).[54, 55] The best yields were observed with NaOH and DBU and in these instances the reactions

Figure 13. Reagents and conditions: PdCl2, NaHCO3 (1.2 equiv.), Bu4NBr, 120 ºC, 24 h.

Figure 14. Reagents and conditions: [Bu4N]Br, NaOAc, NaHCO3, 130 ºC, Pd-cat.

Motevalli's *N*-(diphenylphosphino)triethylammonium chloride (**IL1**) and *N*-(diphenylphos‐ phino)tributylammonium chloride (**IL2**), have been used successfully in Heck couplings of

**Figure 3.** Structures of *N*-(diphenylphosphino)triethylammonium chloride (**IL1**) and *N*-(diphenylphosphino)tributy‐

The coupling of electron poor chloroarenes with mono and di-substituted olefins across a range of RTILs and Pd-sources has been examined.[57] The model system, resulting in the synthesis of stilbene from chlorobenzene and styrene was best conducted with simple, e.g. PdCl2, phospha-based Pd-sources (Scheme 13). RTILs examined included: imidazolium, ammonium and phosphonium salts. The tetraalkylammonium salts, in particular [Bu4N][Br], were superior permitting the coupling of chloroarenes in the presence of less active catalysts such as PdCl2 and Pd(Ph3P)4. Regardless of the conditions used, all imidazolium based RTILs gave poor results, e.g. 22 % for [bmim][BF4] and 13 % for [bmim][Br] whereas TBAB gave 72 % of the desired

**2.4. Studies using imidazolium, pyridinium, phosphonium and ammonium RTILs**

stilbene. With [bmim][BF4] there was clear evidence of the formation of Pd black.[57]

Figure 12. Reagents and conditions: PdCl2, NaHCO3, Bu4NBr, 120 ºC, 24 h.

Figure 13. Reagents and conditions: PdCl2, NaHCO3 (1.2 equiv.), Bu4NBr, 120 ºC, 24 h.

Figure 14. Reagents and conditions: [Bu4N]Br, NaOAc, NaHCO3, 130 ºC, Pd-cat.

(Scheme 11) and allowed catalyst reuse.[53]

Figure 11. Reagents and conditions: Pd(OAc)2, *n*-Bu4NOAc/*n*-Bu4NBr, 100 ºC.

reactions were complete in < 30 min.

**Sheme 11.** Reagents and conditions: PdCl2, NaHCO3 (1.2 equiv.), Bu4NBr, 120 °C, 24 h.

reactions were complete in < 30 min.

**Sheme 12.** Reagents and conditions: [Bu4N]Br, NaOAc, NaHCO3, 130 °C, Pd-cat.

iodobenzene and styrene (Figure 3 and Table 3).[56]

(Scheme 11) and allowed catalyst reuse.[53]

were complete in < 30 min.

36 Ionic Liquids - Current State of the Art

lammonium chloride (**IL2**).

**Sheme 13.** Reagents and conditions: PdCl2 or Pd(Ph3P)4, 150 °C, [bmim][BF4] or [bmim]Br or Bu4NBr reaction of mono and di-substituted olefins in a diversity of RTILs.

Heck couplings have also been conducted in the thermally and chemically stable [P6,6,6,14][X] quaternary phosphonium salts, where X=Br- , Cl- , I- , BF4 and CH2(CH2)8CO2 and the resulting FILs used in the coupling of iodobenzene with methylacrylate.[58] The effect of anion on the coupling outcome was determined by screening using Pd2dba3.CHCl3 and each of the phos‐ phonium FILs in turn. High coupling efficiency was observed [P6,6,6,14][CH2(CH2)8CO2] (75%) and [P6,6,6,14][Cl] (78%), with [P6,6,6,14][Cl] also providing a simpler work up.

The coupling of bromobenzene and butyl acrylate was examined in a range of what were designated, non-aqueous ionic liquids (NAILs), with *trans*-di(μ-acetato)-bis[o-(di-*o*-tolylphos‐ phino)benzyl] dipalladium(II) as catalyst (Scheme 14).[59, 60] These NAILs were drawn from Bu4NBr, Bu4NOAc, 1-methyl-3-propylimidazolium bromide ([MPIM]Br), tri-*n*-butyl-*n*hexadecylphosphonium bromide (TBHDP), triphenylmethylphosphonium chloride (TPMPC) and triphenylmethylphosphonium bromide (TPMPB), all of which gave homogeneous reaction media and permitted facile catalyst recycling.

**Sheme 14.** Reagents and conditions: 0.5% Pd-cat, NAIL.

#### **3. Functionalized Ionic Liquids (FILs)**

Functionalised (FILs) or, as they are sometimes know, task specific ionic liquids, incorporate additional functional moieties within the cation or anion.[61] FILs can be discrete liquids or be supported reagents and have applications as reagents and catalysts.[62]- [66] FILs have been examined as novel media for the Pd(OAc)2 mediated Heck reaction of 2-methylprop-2-en-1-ol and 4-*tert*-butyliodobenzene in [*i*Pr2N(CH2)2.mim][NTf2] and [iPr2N(CH2)2O(CH2)2N112][NTf2]. In [Pr2N(CH2)2.mim][NTf2] only 32 % of 3-(4-*tert*-butylphenyl)-2-methylpropanal (β-Lilial®) was present after 10 h; this increased to 84% on using [*i*Pr2N(CH2)2O(CH2)2N112][NTf2]. These outcomes correlate well with the relative basicity of these two FILs. The equivalent coupling in neat Hünig's base showed a conversion of 39%, supporting a catalytic role for the PILs.[67] The selectivity between 3-(4-*tert*-butylphenyl)-2-methylpropanal and 2-(4-*tert*-butylphenyl)-3 methylpropanal was found to be >95% respect to β-Lilial® and independent of the PIL basicity (Scheme 15).

**Sheme 15.** Reagents and conditions: Pd(OAc)2, 95 °C, time, base tethered-RTIL.

RTILs based on dialkylimidazolium salts have attracted particular attention, as they are easy to prepare and handle, having good solubility for many substrates and molecular catalyst and are readily synthesised through a variety of green chemistry approaches.[68]- [70] 1-Octyl-3 methylimidazolium nonafluorobutanesulfonate [omim][FNBS] represents a novel dialkylimi‐ dazolium based hydrophobic ionic liquid which is effective in ligand-free Heck couplings with electron deficient olefins (Scheme 16).[71]

**Sheme 16.** Reagents and conditions: Pd(OAc)2, Et3N, [omim][NFBS], 100 °C, 3-12 h.

Nitrile modified imidazolium and pyridinium salts have been used in Pd-catalysed crosscoupling reactions (Scheme 17).[72, 73] These FILs are highly effective solvents for the Heck reaction with excellent yields observed (Table 4).[74]

**Sheme 17.** Reagents and conditions: 5 mol % Pd, [C3CNmim][Tf2N], 80 °C, 12 h.


**3. Functionalized Ionic Liquids (FILs)**

38 Ionic Liquids - Current State of the Art

(Scheme 15).

Functionalised (FILs) or, as they are sometimes know, task specific ionic liquids, incorporate additional functional moieties within the cation or anion.[61] FILs can be discrete liquids or be

examined as novel media for the Pd(OAc)2 mediated Heck reaction of 2-methylprop-2-en-1-ol and 4-*tert*-butyliodobenzene in [*i*Pr2N(CH2)2.mim][NTf2] and [iPr2N(CH2)2O(CH2)2N112][NTf2]. In [Pr2N(CH2)2.mim][NTf2] only 32 % of 3-(4-*tert*-butylphenyl)-2-methylpropanal (β-Lilial®) was present after 10 h; this increased to 84% on using [*i*Pr2N(CH2)2O(CH2)2N112][NTf2]. These outcomes correlate well with the relative basicity of these two FILs. The equivalent coupling in neat Hünig's base showed a conversion of 39%, supporting a catalytic role for the PILs.[67] The selectivity between 3-(4-*tert*-butylphenyl)-2-methylpropanal and 2-(4-*tert*-butylphenyl)-3 methylpropanal was found to be >95% respect to β-Lilial® and independent of the PIL basicity

RTILs based on dialkylimidazolium salts have attracted particular attention, as they are easy to prepare and handle, having good solubility for many substrates and molecular catalyst and

methylimidazolium nonafluorobutanesulfonate [omim][FNBS] represents a novel dialkylimi‐ dazolium based hydrophobic ionic liquid which is effective in ligand-free Heck couplings with

Nitrile modified imidazolium and pyridinium salts have been used in Pd-catalysed crosscoupling reactions (Scheme 17).[72, 73] These FILs are highly effective solvents for the Heck

are readily synthesised through a variety of green chemistry approaches.[68]-

[66] FILs have been

[70] 1-Octyl-3-

supported reagents and have applications as reagents and catalysts.[62]-

**Sheme 15.** Reagents and conditions: Pd(OAc)2, 95 °C, time, base tethered-RTIL.

**Sheme 16.** Reagents and conditions: Pd(OAc)2, Et3N, [omim][NFBS], 100 °C, 3-12 h.

**Sheme 17.** Reagents and conditions: 5 mol % Pd, [C3CNmim][Tf2N], 80 °C, 12 h.

reaction with excellent yields observed (Table 4).[74]

electron deficient olefins (Scheme 16).[71]

**Table 4.** Selected examples of the Heck Coupling of Iodobenzene with ethyl acrylate in [C3CNmim][Tf2N] at 80 **°**C.

Numerous studies have highlighted the deprotonation of imidazolium RTILs to yield an imidazol-2-ylidene *N*-heterocyclic carbene (NHC) as a crucial step in subsequent reactions complex generated by deprotonation of the ionic liquid cation.[75-78] Many transition-metal carbene complexes have been prepared and their catalytic applications described.[79, 80] This has led to the evaluation of novel RTILs as catalysts in Pd-coupling reactions.[81, 82] Metal-NHC complexes have been generated and examined in RTILs, with the metal-NHC complex reactivity examined for Heck coupling efficacy in DMF and [bmim][NTf2] based of an NHC located from an ionic liquid cation and investigate the catalytic activity in both molecular and ionic liquid solvents in the Heck coupling of butyl acrylate and bromobenzene (Scheme 18). [83-86]

**Sheme 18.** Reagents and conditions: 5 mol% Pd-cat, Cs2CO3, [Bmim][NTf2], 150 °C, 18 h.

Fructose has been used as a renewable resource in the synthesis of novel hydroxymethylimi‐ dazolium based protic ionic liquids (PILs) (Scheme 19).[86-91]

**Sheme 19.** Reagents and conditions: (i) NH2, CH2O, CuCO3; (ii) BuBr, KOtBu, EtOH; (iii) MeI, CH2Cl2; Metal-X.

Use of these fructose derived PILs in the Pd(OAc)2 mediated Heck coupling of methyl acrylate with iodobenzene afforded rapid conversion (1 h) to methyl cinnamate in > 95% yield at 100 °C (Scheme 20). Both the PIL and catalyst were readily recycled with no loss of activity.

**Sheme 20.** Reagents and conditions: 2 mol % Pd(OAc)2, Et3N, RTIL, 100 °C.

Shreev, *et al*, synthesized the new RTIL, shown in (Scheme 21), which contain the dication 1,1' methylene-3,3'-dialkylbis(imidazolium) or 1,1'-methylene-4,'-dialkylbis(1,2,4-triazolium) with NTf2 as the anion, and evaluated its efficacy in the Heck reaction (Table 5).[92]

**Sheme 21.** Reagents and conditions: (i) CH2Cl2 or CH2Br2, KOH, Bu4NBr; (ii) RI, 110-130 °C, 20; (iii) LiN(SO2CF3)2, CH3OH/H2O (10:1), RT, 2 h.


**Table 5.** Heck cross-coupling reactions in the ionic liquid-**3** and different anions (X) with selected aryl halides and butyl acrylate.

In a related study Shreeve *et al*, also examined the use of a range basic RTILs as both the base and solvent for the Heck coupling of iodobenzene and butyl acrylate (see Figure 3 for chemical structutures of the BILs). With BILs, **BIL-1**, **BIL-2** and **BIL-3** quantitative conversion and regioselectivity was observed. All other BILs (**BIL-4**-**BIL-8**) displayed low to no reactivity under the conditions examined (Table 6). In this study, these results suggest that RTILs with pendant aliphatic tertiary amines are superior to the pyridinium salts.[93]

**Figure 4.** Chemical structures of Basic ionic liquid cations.

Shreev, *et al*, synthesized the new RTIL, shown in (Scheme 21), which contain the dication 1,1' methylene-3,3'-dialkylbis(imidazolium) or 1,1'-methylene-4,'-dialkylbis(1,2,4-triazolium)

**Sheme 21.** Reagents and conditions: (i) CH2Cl2 or CH2Br2, KOH, Bu4NBr; (ii) RI, 110-130 °C, 20; (iii) LiN(SO2CF3)2,

Entry Pd source R X Time (h) Yield % PdCl2 H I 6 92 PdCl2 H Br 18 71 PdCl2 H Cl 24 3 PdCl2 NO2 Br 18 69 PdCl2 CF3 Br 18 57 PdCl2 CH3 Br 12 76

**Table 5.** Heck cross-coupling reactions in the ionic liquid-**3** and different anions (X) with selected aryl halides and

In a related study Shreeve *et al*, also examined the use of a range basic RTILs as both the base and solvent for the Heck coupling of iodobenzene and butyl acrylate (see Figure 3 for chemical structutures of the BILs). With BILs, **BIL-1**, **BIL-2** and **BIL-3** quantitative conversion and regioselectivity was observed. All other BILs (**BIL-4**-**BIL-8**) displayed low to no reactivity

CH3OH/H2O (10:1), RT, 2 h.

40 Ionic Liquids - Current State of the Art

butyl acrylate.

with NTf2 as the anion, and evaluated its efficacy in the Heck reaction (Table 5).[92]

**Table 6.** Heck reactions between butyl acrylate and iodobenzene in the presence of basic ionic liquid (**BIL1**-**BIL8**) (Fig. 3).

The novel imidazolium RTIL tagged Pd-Schiff base complex was active in both Heck and Suzuki couplings in aqueous media. Relative to other Pd-catalysted reactions in aqueous media, this catalyst was effective in the coupling of water insoluble aryl halides without the aid of a phase transfer catalyst or organic solvents (Scheme 22).[94] Optimised Heck coupling conditions required the use of 1 mol % catalyst, K2CO3 and with iodobenznene and cyclohexyl acrylate gave benzyl cinnamate in 96% yield, (Scheme 23).

Chitosan supported Pd(OAc)2 nanoparticles (Pd-NP) in TBAB with added tetrabutyl ammo‐ nium acetate (TBAA) gave rise to very rapid Heck couplings of aryl bromides, iodides and activated chlorides (Scheme 23).[95] The supported catalyst was amenable to multiple recycles, whereas the free nano particles rapidly lost activity.

**Sheme 22.** Reagents and conditions: (i) BrCH2CH2CH2Br, acetone, NaHCO3, 60 °C, 60 h; *N*-methylimidazole, 80 °C, 48 h; (iii) aniline, EtOH, reflux, 4 h; Pd(OAc)2; (iv) H2O, imidazolium ILs, 80 °C and 4 h; (v) RTIL, 80 °C, K2CO3.

**Sheme 23.** Reagents and conditions: Pd-NP /chitosan, [Bu4N][Br]/[Bu4N][OAc], 15 min to 1.5 h, 130 °C.

With Pd-NP in a mixture of [Bu4N][Br]/[Bu4N][OAc] it was possible to couple 1-bromo-4 chlorobenzene with two different olefins in a one-pot sequential manner by activating the C-Br and C-Cl bonds on the aromatic ring at two different temperatures of 100 and 120 °C (Scheme 24).[96]

**Sheme 24.** Reagents and conditions: (i) butyl acrylate, Pd-NP, [Bu4N][Br]/[Bu4N][OAc], 100 °C, 30 min; (ii) styrene, Pd-NP, [Bu4N][Br]/[Bu4N][OAc], 120 °C, 30 min.

There have been multiple reports on the use of nitrile-functionalized RTILs, such as the imidazolium and pyridinium based systems, in Pd-catalysed reactions, including the Heck reaction. Heck coupling in these FILs typically afforded a 90% isolated yield of the desired product (Scheme 25).[97, 98]

**Sheme 25.** Reagents and Conditions: 5 mol % Pd-cat; IL, 80 °C, 12 h.

#### **3.1. Chiral Ionic Liquids (CIL)**

**Sheme 23.** Reagents and conditions: Pd-NP /chitosan, [Bu4N][Br]/[Bu4N][OAc], 15 min to 1.5 h, 130 °C.

24).[96]

42 Ionic Liquids - Current State of the Art

NP, [Bu4N][Br]/[Bu4N][OAc], 120 °C, 30 min.

product (Scheme 25).[97, 98]

With Pd-NP in a mixture of [Bu4N][Br]/[Bu4N][OAc] it was possible to couple 1-bromo-4 chlorobenzene with two different olefins in a one-pot sequential manner by activating the C-Br and C-Cl bonds on the aromatic ring at two different temperatures of 100 and 120 °C (Scheme

**Sheme 22.** Reagents and conditions: (i) BrCH2CH2CH2Br, acetone, NaHCO3, 60 °C, 60 h; *N*-methylimidazole, 80 °C, 48

h; (iii) aniline, EtOH, reflux, 4 h; Pd(OAc)2; (iv) H2O, imidazolium ILs, 80 °C and 4 h; (v) RTIL, 80 °C, K2CO3.

**Sheme 24.** Reagents and conditions: (i) butyl acrylate, Pd-NP, [Bu4N][Br]/[Bu4N][OAc], 100 °C, 30 min; (ii) styrene, Pd-

There have been multiple reports on the use of nitrile-functionalized RTILs, such as the imidazolium and pyridinium based systems, in Pd-catalysed reactions, including the Heck reaction. Heck coupling in these FILs typically afforded a 90% isolated yield of the desired To date the use of chiral RTILs (CILs) in Heck couplings has met with limited success. The arylation of 2,3-dihydrofuran with iodobenzene catalysed by a chiral pyridinium ILs with [PdCl4 2-] (Figure 4), (used as a co-solvent with [bmim][PF6]), (Scheme 26).[99]

**Sheme 26.** Reagents and conditions: 2,3-dihydrofuran with iodobenzene catalysed by CILs with [PdCl4 2-], Et3N, [bmim]PF6, 100 °C.

However, the use of the chiral [bmim][PF6], did give rise to the desired 7-benzyloxy-2*H*chromene in good yield and modest e.e. (15%) (Scheme 27).[100]

**Sheme 27.** Reagents and conditions: The oxyarylation of 7-benzyloxy-2*H*-chromene in CILs, Pd(OAc)2, Ag2CO3, 100 °C and 4 h.

#### **3.2. Supported ionic liquid phase (SILP) catalyst system**

Immobilisation of the Pd-catalyst and the RTIL onto high surface area porous solids such as silica yields a supported ionic liquid phase (SILP) catalyst system. SLIPs are considered, while being solids, to contain the active species comprise solubilized in the IL phase behaving as a homogeneous catalyst, and as such offer the potential for novel reactivity. Suzuki has examined this reactivity with a range of Pd(OAc)2/silica based SLIP catalyst systems. The SLIPs were air and thermally stable, provided simple storage conditions, easily recyclable and highly effective in the Heck coupling of substituted arylhalides with vinyl esters (Scheme 28).[101, 102]

**Sheme 28.** Reagents and conditions: Pd(OAc)2, SILP, Na[(Ph)2P-(*m*-PhSO3)], 150 °C, 7-17 h.

In a related study, Pd(OAc)2 and [bmim][PF6] were immobilized on reversed phase silica gels such as aminopropylated or *N*,*N*-diethylaminopropylated silica.[103] The Heck reaction between iodobenzene and cyclohexyl acrylate was carried out as shown in (Scheme 29). The catalyst was reused five times with no loss of catalytic activity.

**Sheme 29.** Reagents and conditions: Pd(OAc)2, [bmim][PF6]-SiO2, 30 °C, 1.5-3 h.

Yokoyama *et al*, has been reported the use of a SiO2 supported Pd(II)/[bmim][PF6] as a highly active and reusable SLIP for the phosphine free Heck reaction of iodobenzene and ethyl acrylate (Scheme 30).[104] The addition of low levels of Et3N increased the [bmim][PF6] decomposition temperature in this system from 130 to 160 °C.

**Sheme 30.** Reagents and conditions: Pd(II)-SiO/[bmim][PF6], Pd/SiO2, Et3N, [bmim][PF6], 130-160 °C, 24 h.

#### **3.3. Ultrasonic synthesis approaches**

In the RTILs, 1,3-di-*n*-butylimidazolium bromide [bbim][Br] and 1,3-di-*n*-butylimidazolium tetrafluoroborate [bbim][BF4], under ultrasonic irradiation significant rate enhancements were noted for the NaOAc / PdCl2 mediated coupling of substituted iodobenzenes with alkenes/ alkynes at 120 oC (Scheme 31).[105] Isolated yields were good to excellent (up to 87%) with only the *trans* product obtained. These couplings only required 1.5-3 h.

#### **3.4. Microwave synthesis approaches**

Microwave heating has been applied to the Heck reaction in RTILs significantly reducing the time required to effect coupling, and influencing product yield and the extent of by-product generation.[106, 110] Generally microwave approaches have focused on the use of aryl iodides Microwave heating has been applied to the Heck reaction in RTILs significantly reducing the time required to effect

formations without the phosphine ligand. This system was recyclable at least five times, and the volatile product was

**3.4. Microwave synthesis approaches Sheme 31.** Reagents and conditions: (i) 2 mol% PdCl2, [bbim][Br] or [bbim][BF4], 120 °C, 1.5-3 h.

**Sheme 28.** Reagents and conditions: Pd(OAc)2, SILP, Na[(Ph)2P-(*m*-PhSO3)], 150 °C, 7-17 h.

catalyst was reused five times with no loss of catalytic activity.

44 Ionic Liquids - Current State of the Art

**Sheme 29.** Reagents and conditions: Pd(OAc)2, [bmim][PF6]-SiO2, 30 °C, 1.5-3 h.

decomposition temperature in this system from 130 to 160 °C.

**3.3. Ultrasonic synthesis approaches**

**3.4. Microwave synthesis approaches**

In a related study, Pd(OAc)2 and [bmim][PF6] were immobilized on reversed phase silica gels such as aminopropylated or *N*,*N*-diethylaminopropylated silica.[103] The Heck reaction between iodobenzene and cyclohexyl acrylate was carried out as shown in (Scheme 29). The

Yokoyama *et al*, has been reported the use of a SiO2 supported Pd(II)/[bmim][PF6] as a highly active and reusable SLIP for the phosphine free Heck reaction of iodobenzene and ethyl acrylate (Scheme 30).[104] The addition of low levels of Et3N increased the [bmim][PF6]

**Sheme 30.** Reagents and conditions: Pd(II)-SiO/[bmim][PF6], Pd/SiO2, Et3N, [bmim][PF6], 130-160 °C, 24 h.

only the *trans* product obtained. These couplings only required 1.5-3 h.

In the RTILs, 1,3-di-*n*-butylimidazolium bromide [bbim][Br] and 1,3-di-*n*-butylimidazolium tetrafluoroborate [bbim][BF4], under ultrasonic irradiation significant rate enhancements were noted for the NaOAc / PdCl2 mediated coupling of substituted iodobenzenes with alkenes/ alkynes at 120 oC (Scheme 31).[105] Isolated yields were good to excellent (up to 87%) with

Microwave heating has been applied to the Heck reaction in RTILs significantly reducing the time required to effect coupling, and influencing product yield and the extent of by-product generation.[106, 110] Generally microwave approaches have focused on the use of aryl iodides

and active aryl bromide, such as those reported by Larhed *et al* in [bmim][PF6] (Scheme 32). [111] Using 4 mol % PdCl2 (4 mol %), P(*o*-tolyl)3 as the added Pd-ligand, reactions were complete after 5-45 min, at 180 – 220 °C. The catalyst system and RTIL were and the time 20 minutes and 45 minutes for trans formations without the phosphine ligand. This system was recyclable at least five times, and the volatile product was directly isolated in high yield by rapid distillation under reduced pressure.[111] coupling, and influencing product yield and the extent of by-product generation.[106],[110] Generally microwave approaches have focused on the use of aryl iodides and active aryl bromide, such as those reported by Larhed *et al* in [bmim][PF6] (Scheme 32).[111] Using 4 mol % PdCl2 (4 mol %), P(*o*-tolyl)3 as the added Pd-ligand, reactions were complete after 5-45 min, at 180 – 220 ºC. The catalyst system and RTIL were and the time 20 minutes and 45 minutes for trans formations without the phosphine ligand. This system was recyclable at least five times, and the volatile product was directly isolated in high yield by rapid distillation under reduced pressure.[111] Microwave heating has been applied to the Heck reaction in RTILs significantly reducing the time required to effect coupling, and influencing product yield and the extent of by-product generation.[106],[110] Generally microwave approaches have focused on the use of aryl iodides and active aryl bromide, such as those reported by Larhed *et al* in [bmim][PF6] (Scheme 32).[111] Using 4 mol % PdCl2 (4 mol %), P(*o*-tolyl)3 as the added Pd-ligand, reactions were complete after 5-45 min, at 180 – 220 ºC. The catalyst system and RTIL were and the time 20 minutes and 45 minutes for trans

Sheme 32.Reagents and conditions: PdCl2, P(*o*-tolyl)3, Et3N, [bmim][PF6], W, 180-220 ºC, 5-45 min. **Sheme 32.** Reagents and conditions: PdCl2, P(*o*-tolyl)3, Et3N, [bmim][PF6], μW, 180-220 °C, 5-45 min.

More complex Pd-catalysis such as Herman's palladacycle, *trans*-di(μ-acetato)bis[*o*-di-*o*-tolylphosphanyl) benzyl]dipalladium, have been developed in efforts to enhance Pd-coupling outcomes with unreactive aryl chlorides.[112] Using this Pd-catalyst (1.5 – 10 mol %), Heck coupling in [bmim][PF6] / dioxane mixtures with aryl chlorides and butyl acrylate gave the desired cinnamic esters.[113] High levels of phosphine ligand (3-20 %) were required dependent on the reactivity of the aryl chloride. Under microwave irradiation the yields were moderate to excellent (Scheme 33).[114] More complex Pd-catalysis such as Herman's palladacycle, *trans*-di(μ-acetato)bis[*o*-di-*o*tolylphosphanyl)-benzyl]dipalladium, have been developed in efforts to enhance Pd-coupling outcomes with unreactive aryl chlorides.[112] Using this Pd-catalyst (1.5 – 10 mol %), Heck coupling in [bmim][PF6] / dioxane mixtures with aryl chlorides and butyl acrylate gave the desired cinnamic esters.[113] High levels of phosphine ligand (3-20 %) were required depend‐ ent on the reactivity of the aryl chloride. Under microwave irradiation the yields were moderate to excellent (Scheme 33).[114] Sheme 32.Reagents and conditions: PdCl2, P(*o*-tolyl)3, Et3N, [bmim][PF6], W, 180-220 ºC, 5-45 min. More complex Pd-catalysis such as Herman's palladacycle, *trans*-di(μ-acetato)bis[*o*-di-*o*-tolylphosphanyl) benzyl]dipalladium, have been developed in efforts to enhance Pd-coupling outcomes with unreactive aryl chlorides.[112] Using this Pd-catalyst (1.5 – 10 mol %), Heck coupling in [bmim][PF6] / dioxane mixtures with aryl chlorides and butyl acrylate gave the desired cinnamic esters.[113] High levels of phosphine ligand (3-20 %) were required dependent on the reactivity of the aryl chloride. Under microwave irradiation the yields were moderate to excellent (Scheme 33).[114]

Microwave irradiation of [omim][BF4] with 3-5 mol % Pd/C proved effective in the phosphine free Heck coupling of aryl iodides and aryl bromides with butyl acrylate. The reactions were typically complete in 1.5 min affording 33-89% yield of Sheme 33. Reagents and conditions: Herrmann's palladacycle, [(*<sup>t</sup>* Bu)3PH][BF4], Cy2NMe, [bmim][PF6]/dioxane, W, 180 ºC, 30-60 min. **Sheme 33.** Reagents and conditions: Herrmann's palladacycle, [(*<sup>t</sup>* Bu)3PH][BF4], Cy2NMe, [bmim][PF6]/dioxane, μW, 180 °C, 30-60 min.

the *trans*-butyl cinnamates. This microwave based Pd-coupling approach was effective across a range of olefinic substrates including styrene, 2-methylbutyl acrylate and methyl cinnamate with iodobenzene. The steric bulk of the olefin affected reaction outcome with yields ranging from 27 – 86 % (Scheme 34).[115] Microwave irradiation of [omim][BF4] with 3-5 mol % Pd/C proved effective in the phosphine free Heck coupling of aryl iodides and aryl bromides with butyl acrylate. The reactions were typically complete in 1.5 min affording 33-89% yield of the *trans*-butyl cinnamates. This microwave based Pd-coupling approach was effective across a range of olefinic substrates including styrene, 2-methylbutyl acrylate and methyl cinnamate with iodobenzene. The steric bulk of the Microwave irradiation of [omim][BF4] with 3-5 mol % Pd/C proved effective in the phosphine free Heck coupling of aryl iodides and aryl bromides with butyl acrylate. The reactions were typically complete in 1.5 min affording 33-89% yield of the *trans*-butyl cinnamates. This

Sheme 34.Reagents and conditions: Pd/C, (n-Bu)3N, [omim][BF4], W, 1.5 min at 375W.

olefin affected reaction outcome with yields ranging from 27 – 86 % (Scheme 34).[115]

activity.[116]

activity.[116]

Sheme 34.Reagents and conditions: Pd/C, (n-Bu)3N, [omim][BF4], W, 1.5 min at 375W.

Under conventional heating for 24 h, the Heck coupling of iodobenzene with ethyl acrylate in 1-(2-cyanoethyl)-3-(2 hydroxyethyl)-1*H*-imidazol-3-ium tetrafluoroborate, afforded a modest 25% yield of ethyl cinnamate with PdCl2. Using microwave irradiation (200 W, 120 ºC), the same reaction system gave 88% yields of ethyl cinnamate in 5 min (Scheme 35). The system showed good stability and maintained the efficiency after six consecutive runs without significant loss of

Sheme 35.Reagents and conditions: PdCl2, RTIL, W, 120 ºC, 5-20 min.

Sheme 35.Reagents and conditions: PdCl2, RTIL, W, 120 ºC, 5-20 min.

Under conventional heating for 24 h, the Heck coupling of iodobenzene with ethyl acrylate in 1-(2-cyanoethyl)-3-(2 hydroxyethyl)-1*H*-imidazol-3-ium tetrafluoroborate, afforded a modest 25% yield of ethyl cinnamate with PdCl2. Using microwave irradiation (200 W, 120 ºC), the same reaction system gave 88% yields of ethyl cinnamate in 5 min (Scheme 35). The system showed good stability and maintained the efficiency after six consecutive runs without significant loss of microwave based Pd-coupling approach was effective across a range of olefinic substrates including styrene, 2-methylbutyl acrylate and methyl cinnamate with iodobenzene. The steric bulk of the olefin affected reaction outcome with yields ranging from 27 – 86 % (Scheme 34). [115] iodides and aryl bromides with butyl acrylate. The reactions were typically complete in 1.5 min affording 33-89% yield of the *trans*-butyl cinnamates. This microwave based Pd-coupling approach was effective across a range of olefinic substrates including styrene, 2-methylbutyl acrylate and methyl cinnamate with iodobenzene. The steric bulk of the olefin affected reaction outcome with yields ranging from 27 – 86 % (Scheme 34).[115]

Sheme 31. Reagents and conditions: (i) 2 mol% PdCl2, [bbim][Br] or [bbim][BF4], 120 ºC, 1.5-3 h.

directly isolated in high yield by rapid distillation under reduced pressure.[111]

Microwave heating has been applied to the Heck reaction in RTILs significantly reducing the time required to effect coupling, and influencing product yield and the extent of by-product generation.[106],[110] Generally microwave approaches have focused on the use of aryl iodides and active aryl bromide, such as those reported by Larhed *et al* in [bmim][PF6] (Scheme 32).[111] Using 4 mol % PdCl2 (4 mol %), P(*o*-tolyl)3 as the added Pd-ligand, reactions were complete after 5-45 min, at 180 – 220 ºC. The catalyst system and RTIL were and the time 20 minutes and 45 minutes for trans formations without the phosphine ligand. This system was recyclable at least five times, and the volatile product was

More complex Pd-catalysis such as Herman's palladacycle, *trans*-di(μ-acetato)bis[*o*-di-*o*-tolylphosphanyl) benzyl]dipalladium, have been developed in efforts to enhance Pd-coupling outcomes with unreactive aryl chlorides.[112]

acrylate gave the desired cinnamic esters.[113] High levels of phosphine ligand (3-20 %) were required dependent on the reactivity of the aryl chloride. Under microwave irradiation the yields were moderate to excellent (Scheme 33).[114]

Sheme 32.Reagents and conditions: PdCl2, P(*o*-tolyl)3, Et3N, [bmim][PF6], W, 180-220 ºC, 5-45 min.

Microwave heating has been applied to the Heck reaction in RTILs significantly reducing the time required to effect coupling, and influencing product yield and the extent of by-product generation.[106],[110] Generally microwave approaches have focused on the use of aryl iodides and active aryl bromide, such as those reported by Larhed *et al* in [bmim][PF6] (Scheme 32).[111] Using 4 mol % PdCl2 (4 mol %), P(*o*-tolyl)3 as the added Pd-ligand, reactions were complete after 5-45 min, at 180 – 220 ºC. The catalyst system and RTIL were and the time 20 minutes and 45 minutes for trans formations without the phosphine ligand. This system was recyclable at least five times, and the volatile product was

More complex Pd-catalysis such as Herman's palladacycle, *trans*-di(μ-acetato)bis[*o*-di-*o*-tolylphosphanyl) benzyl]dipalladium, have been developed in efforts to enhance Pd-coupling outcomes with unreactive aryl chlorides.[112] Using this Pd-catalyst (1.5 – 10 mol %), Heck coupling in [bmim][PF6] / dioxane mixtures with aryl chlorides and butyl acrylate gave the desired cinnamic esters.[113] High levels of phosphine ligand (3-20 %) were required dependent on the

Microwave irradiation of [omim][BF4] with 3-5 mol % Pd/C proved effective in the phosphine free Heck coupling of aryl

Bu)3PH][BF4], Cy2NMe, [bmim][PF6]/dioxane, W, 180 ºC, 30-60 min.

reactivity of the aryl chloride. Under microwave irradiation the yields were moderate to excellent (Scheme 33).[114]

**3.4. Microwave synthesis approaches** 

Sheme 31. Reagents and conditions: (i) 2 mol% PdCl2, [bbim][Br] or [bbim][BF4], 120 ºC, 1.5-3 h.

directly isolated in high yield by rapid distillation under reduced pressure.[111]

Sheme 32.Reagents and conditions: PdCl2, P(*o*-tolyl)3, Et3N, [bmim][PF6], W, 180-220 ºC, 5-45 min.

**3.4. Microwave synthesis approaches** 

olefin affected reaction outcome with yields ranging from 27 – 86 % (Scheme 34).[115]

Sheme 34.Reagents and conditions: Pd/C, (n-Bu)3N, [omim][BF4], W, 1.5 min at 375W. **Sheme 34.** Reagents and conditions: Pd/C, (n-Bu)3N, [omim][BF4], μW, 1.5 min at 375W.

Under conventional heating for 24 h, the Heck coupling of iodobenzene with ethyl acrylate in 1-(2-cyanoethyl)-3-(2 hydroxyethyl)-1*H*-imidazol-3-ium tetrafluoroborate, afforded a modest 25% yield of ethyl cinnamate with PdCl2. Using microwave irradiation (200 W, 120 ºC), the same reaction system gave 88% yields of ethyl cinnamate in 5 min (Scheme 35). The system showed good stability and maintained the efficiency after six consecutive runs without significant loss of activity.[116] Under conventional heating for 24 h, the Heck coupling of iodobenzene with ethyl acrylate in 1-(2-cyanoethyl)-3-(2-hydroxyethyl)-1*H*-imidazol-3-ium tetrafluoroborate, afforded a modest 25% yield of ethyl cinnamate with PdCl2. Using microwave irradiation (200 W, 120 °C), the same reaction system gave 88% yields of ethyl cinnamate in 5 min (Scheme 35). The system showed good stability and maintained the efficiency after six consecutive runs without significant loss of activity.[116] Sheme 34.Reagents and conditions: Pd/C, (n-Bu)3N, [omim][BF4], W, 1.5 min at 375W. Under conventional heating for 24 h, the Heck coupling of iodobenzene with ethyl acrylate in 1-(2-cyanoethyl)-3-(2 hydroxyethyl)-1*H*-imidazol-3-ium tetrafluoroborate, afforded a modest 25% yield of ethyl cinnamate with PdCl2. Using microwave irradiation (200 W, 120 ºC), the same reaction system gave 88% yields of ethyl cinnamate in 5 min (Scheme 35). The system showed good stability and maintained the efficiency after six consecutive runs without significant loss of

Sheme 35.Reagents and conditions: PdCl2, RTIL, W, 120 ºC, 5-20 min. **Sheme 35.** Reagents and conditions: PdCl2, RTIL, μW, 120 °C, 5-20 min.

activity.[116]

Sheme 35.Reagents and conditions: PdCl2, RTIL, W, 120 ºC, 5-20 min. Under microwave irradiation in TBAB, the {Pd[C6H2(CH2CH2NH2)-(OMe)2,3,4](μ-Br)}2, (palladacylce A) mediated Heck coupling of aryl bromides, aryl iodides, aryl chlorides and arene sulfonyl chlorides increased dramatically with reaction times reducing from hours to minutes (Scheme 36).[117] Under microwave irradiation in TBAB, the {Pd[C6H2(CH2CH2NH2)-(OMe)2,3,4](μ-Br)}2, (palladacylce A) mediated Heck coupling of aryl bromides, aryl iodides, aryl chlorides and arene sulfonyl chlorides increased dramatically with reaction

Sheme 36.Reagents and conditions: palladacycle A, [Bu4N][Br], W, 130 ºC, 1-20 min. **Sheme 36.** Reagents and conditions: palladacycle A, [Bu4N][Br], μW, 130 °C, 1-20 min.

**3.5. Flow chemistry approaches** 

oxidation,[121] and the Heck reaction.[122]

**4. Conclusions** 

complicated substrates and larger scale.

times reducing from hours to minutes (Scheme 36).[117]

dehtdrative Heck coupling approach. The combination of [hmim][Br], [PdCl2(PPh3)2] along with LiCl and the combination of HCO2Na and piperidine and microwave irradiation reduced reaction times to 15 min (Scheme 37).[118] The scope of the Heck olefin precursor has been extended through the use of microwave approached to 2° alcohols in a dehtdrative Heck coupling approach. The combination of [hmim][Br], [PdCl2(PPh3)2] along with LiCl and the combination of HCO2Na and piperidine and microwave irradiation reduced reaction times to 15 min (Scheme 37).[118]

Sheme 37. Reagents and conditions: [hmim][Br], HCO2Na, Pd(OAc)2, PPh3, W, 150 ºC at 15-40 min.

of, and in a single run with catalyst recycling, 115.3g of buyl cinnamate (Scheme 38).[123]

Sheme 38. Reagents and conditions: 0.1-0.5 mL.h-1, [BMIM]NTf2, 130-150 ºC, 10-50 min residence time.

The scope of the Heck olefin precursor has been extended through the use of microwave approached to 2º alcohols in a

Micro reactor technology has and a significant impact on the chemical synthesis and production. This technology has many advantages including: 1) highly efficient material mixing; 2) high volume to area ratio; 3) efficient heat transfers ability; 4) the avoidance of "hot spots" by effective temperature control and mixing; and 5) high operational safety.[119] The transition metal catalysed reactions have been reported by using a micro flow system, such as hydrogenation[120] and

RTILs present a challenge for flow chemistry approaches due to their often-high viscosity. Ryu has examined the use of a low viscosity RTIL, [bmim]NTf2 as well as a high viscosity RTIL, [bmim][PF6].[122] The Heck coupling of iodobenzene with butyl acrylate was sluggish in [bmim][PF6], but the use of [bmim][NTf2] in a CPC CYTOS lab system gave 10 g.h-1

In the last twenty years has shown an increasing interest in applying ionic liquids as green solvents in organic synthesis. This approach has been extended to the palladium-catalysed Heck reactions as a key synthetic protocol for C-C bond formation. Factors affecting this approach including the type of ionic liquid used, the base and the catalyst have been investigated by many research groups. In addition, limited number of microwave-based and flow chemistry based Heck reactions have been reported. Despite these efforts, only simple aryl halides and olefines were used in the reported investigations. Active research in this area is still required to increase the scope of Heck reaction in ILs to involve more combination of HCO2Na and piperidine and microwave irradiation reduced reaction times to 15 min (Scheme 37).[118]

Under microwave irradiation in TBAB, the {Pd[C6H2(CH2CH2NH2)-(OMe)2,3,4](μ-Br)}2, (palladacylce A) mediated Heck coupling of aryl bromides, aryl iodides, aryl chlorides and arene sulfonyl chlorides increased dramatically with reaction

Under microwave irradiation in TBAB, the {Pd[C6H2(CH2CH2NH2)-(OMe)2,3,4](μ-Br)}2, (palladacylce A) mediated Heck coupling of aryl bromides, aryl iodides, aryl chlorides and arene sulfonyl chlorides increased dramatically with reaction

combination of HCO2Na and piperidine and microwave irradiation reduced reaction times to 15 min (Scheme 37).[118]

Sheme 36.Reagents and conditions: palladacycle A, [Bu4N][Br], W, 130 ºC, 1-20 min.

Micro reactor technology has and a significant impact on the chemical synthesis and production. This technology has

Sheme 37. Reagents and conditions: [hmim][Br], HCO2Na, Pd(OAc)2, PPh3, W, 150 ºC at 15-40 min.

investigated by many research groups. In addition, limited number of microwave-based and flow chemistry based Heck reactions have been reported. Despite these efforts, only simple aryl halides and olefines were used in the reported

In the last twenty years has shown an increasing interest in applying ionic liquids as green solvents in organic synthesis.

of, and in a single run with catalyst recycling, 115.3g of buyl cinnamate (Scheme 38).[123]

Sheme 36.Reagents and conditions: palladacycle A, [Bu4N][Br], W, 130 ºC, 1-20 min.

times reducing from hours to minutes (Scheme 36).[117]

times reducing from hours to minutes (Scheme 36).[117]

olefin affected reaction outcome with yields ranging from 27 – 86 % (Scheme 34).[115] Sheme 37. Reagents and conditions: [hmim][Br], HCO2Na, Pd(OAc)2, PPh3, W, 150 ºC at 15-40 min. **Sheme 37.** Reagents and conditions: [hmim][Br], HCO2Na, Pd(OAc)2, PPh3, μW, 150 °C at 15-40 min.

**3.5. Flow chemistry approaches** 

#### **3.5. Flow chemistry approaches**

Bu)3PH][BF4], Cy2NMe, [bmim][PF6]/dioxane, W, 180 ºC, 30-60 min.

microwave based Pd-coupling approach was effective across a range of olefinic substrates including styrene, 2-methylbutyl acrylate and methyl cinnamate with iodobenzene. The steric bulk of the olefin affected reaction outcome with yields ranging from 27 – 86 % (Scheme 34).

Sheme 33. Reagents and conditions: Herrmann's palladacycle, [(*<sup>t</sup>*

Under conventional heating for 24 h, the Heck coupling of iodobenzene with ethyl acrylate in 1-(2-cyanoethyl)-3-(2-hydroxyethyl)-1*H*-imidazol-3-ium tetrafluoroborate, afforded a modest 25% yield of ethyl cinnamate with PdCl2. Using microwave irradiation (200 W, 120 °C), the same reaction system gave 88% yields of ethyl cinnamate in 5 min (Scheme 35). The system showed good stability and maintained the efficiency after six consecutive runs without

Under microwave irradiation in TBAB, the {Pd[C6H2(CH2CH2NH2)-(OMe)2,3,4](μ-Br)}2, (palladacylce A) mediated Heck coupling of aryl bromides, aryl iodides, aryl chlorides and arene sulfonyl chlorides increased dramatically with reaction times reducing from hours to

Sheme 36.Reagents and conditions: palladacycle A, [Bu4N][Br], W, 130 ºC, 1-20 min.

and microwave irradiation reduced reaction times to 15 min (Scheme 37).[118]

The scope of the Heck olefin precursor has been extended through the use of microwave approached to 2° alcohols in a dehtdrative Heck coupling approach. The combination of [hmim][Br], [PdCl2(PPh3)2] along with LiCl and the combination of HCO2Na and piperidine

Sheme 37. Reagents and conditions: [hmim][Br], HCO2Na, Pd(OAc)2, PPh3, W, 150 ºC at 15-40 min.

of, and in a single run with catalyst recycling, 115.3g of buyl cinnamate (Scheme 38).[123]

Sheme 38. Reagents and conditions: 0.1-0.5 mL.h-1, [BMIM]NTf2, 130-150 ºC, 10-50 min residence time.

activity.[116]

activity.[116]

significant loss of activity.[116]

**Sheme 34.** Reagents and conditions: Pd/C, (n-Bu)3N, [omim][BF4], μW, 1.5 min at 375W.

Sheme 35.Reagents and conditions: PdCl2, RTIL, W, 120 ºC, 5-20 min. **Sheme 35.** Reagents and conditions: PdCl2, RTIL, μW, 120 °C, 5-20 min.

times reducing from hours to minutes (Scheme 36).[117]

**Sheme 36.** Reagents and conditions: palladacycle A, [Bu4N][Br], μW, 130 °C, 1-20 min.

**3.5. Flow chemistry approaches** 

oxidation,[121] and the Heck reaction.[122]

**4. Conclusions** 

complicated substrates and larger scale.

Sheme 33. Reagents and conditions: Herrmann's palladacycle, [(*<sup>t</sup>*

olefin affected reaction outcome with yields ranging from 27 – 86 % (Scheme 34).[115]

Sheme 34.Reagents and conditions: Pd/C, (n-Bu)3N, [omim][BF4], W, 1.5 min at 375W.

Sheme 32.Reagents and conditions: PdCl2, P(*o*-tolyl)3, Et3N, [bmim][PF6], W, 180-220 ºC, 5-45 min.

Sheme 31. Reagents and conditions: (i) 2 mol% PdCl2, [bbim][Br] or [bbim][BF4], 120 ºC, 1.5-3 h.

directly isolated in high yield by rapid distillation under reduced pressure.[111]

**3.4. Microwave synthesis approaches** 

Sheme 34.Reagents and conditions: Pd/C, (n-Bu)3N, [omim][BF4], W, 1.5 min at 375W.

Under conventional heating for 24 h, the Heck coupling of iodobenzene with ethyl acrylate in 1-(2-cyanoethyl)-3-(2 hydroxyethyl)-1*H*-imidazol-3-ium tetrafluoroborate, afforded a modest 25% yield of ethyl cinnamate with PdCl2. Using microwave irradiation (200 W, 120 ºC), the same reaction system gave 88% yields of ethyl cinnamate in 5 min (Scheme 35). The system showed good stability and maintained the efficiency after six consecutive runs without significant loss of

Microwave irradiation of [omim][BF4] with 3-5 mol % Pd/C proved effective in the phosphine free Heck coupling of aryl iodides and aryl bromides with butyl acrylate. The reactions were typically complete in 1.5 min affording 33-89% yield of the *trans*-butyl cinnamates. This microwave based Pd-coupling approach was effective across a range of olefinic substrates including styrene, 2-methylbutyl acrylate and methyl cinnamate with iodobenzene. The steric bulk of the

Sheme 35.Reagents and conditions: PdCl2, RTIL, W, 120 ºC, 5-20 min.

coupling of aryl bromides, aryl iodides, aryl chlorides and arene sulfonyl chlorides increased dramatically with reaction

The scope of the Heck olefin precursor has been extended through the use of microwave approached to 2º alcohols in a dehtdrative Heck coupling approach. The combination of [hmim][Br], [PdCl2(PPh3)2] along with LiCl and the combination of HCO2Na and piperidine and microwave irradiation reduced reaction times to 15 min (Scheme 37).[118]

Micro reactor technology has and a significant impact on the chemical synthesis and production. This technology has many advantages including: 1) highly efficient material mixing; 2) high volume to area ratio; 3) efficient heat transfers ability; 4) the avoidance of "hot spots" by effective temperature control and mixing; and 5) high operational safety.[119] The transition metal catalysed reactions have been reported by using a micro flow system, such as hydrogenation[120] and

RTILs present a challenge for flow chemistry approaches due to their often-high viscosity. Ryu has examined the use of a low viscosity RTIL, [bmim]NTf2 as well as a high viscosity RTIL, [bmim][PF6].[122] The Heck coupling of iodobenzene with butyl acrylate was sluggish in [bmim][PF6], but the use of [bmim][NTf2] in a CPC CYTOS lab system gave 10 g.h-1

In the last twenty years has shown an increasing interest in applying ionic liquids as green solvents in organic synthesis. This approach has been extended to the palladium-catalysed Heck reactions as a key synthetic protocol for C-C bond formation. Factors affecting this approach including the type of ionic liquid used, the base and the catalyst have been investigated by many research groups. In addition, limited number of microwave-based and flow chemistry based Heck reactions have been reported. Despite these efforts, only simple aryl halides and olefines were used in the reported investigations. Active research in this area is still required to increase the scope of Heck reaction in ILs to involve more

minutes (Scheme 36).[117] Under microwave irradiation in TBAB, the {Pd[C6H2(CH2CH2NH2)-(OMe)2,3,4](μ-Br)}2, (palladacylce A) mediated Heck

Sheme 31. Reagents and conditions: (i) 2 mol% PdCl2, [bbim][Br] or [bbim][BF4], 120 ºC, 1.5-3 h.

directly isolated in high yield by rapid distillation under reduced pressure.[111]

Microwave heating has been applied to the Heck reaction in RTILs significantly reducing the time required to effect coupling, and influencing product yield and the extent of by-product generation.[106],[110] Generally microwave approaches have focused on the use of aryl iodides and active aryl bromide, such as those reported by Larhed *et al* in [bmim][PF6] (Scheme 32).[111] Using 4 mol % PdCl2 (4 mol %), P(*o*-tolyl)3 as the added Pd-ligand, reactions were complete after 5-45 min, at 180 – 220 ºC. The catalyst system and RTIL were and the time 20 minutes and 45 minutes for trans formations without the phosphine ligand. This system was recyclable at least five times, and the volatile product was

More complex Pd-catalysis such as Herman's palladacycle, *trans*-di(μ-acetato)bis[*o*-di-*o*-tolylphosphanyl) benzyl]dipalladium, have been developed in efforts to enhance Pd-coupling outcomes with unreactive aryl chlorides.[112] Using this Pd-catalyst (1.5 – 10 mol %), Heck coupling in [bmim][PF6] / dioxane mixtures with aryl chlorides and butyl acrylate gave the desired cinnamic esters.[113] High levels of phosphine ligand (3-20 %) were required dependent on the reactivity of the aryl chloride. Under microwave irradiation the yields were moderate to excellent (Scheme 33).[114]

Sheme 32.Reagents and conditions: PdCl2, P(*o*-tolyl)3, Et3N, [bmim][PF6], W, 180-220 ºC, 5-45 min.

Microwave heating has been applied to the Heck reaction in RTILs significantly reducing the time required to effect coupling, and influencing product yield and the extent of by-product generation.[106],[110] Generally microwave approaches have focused on the use of aryl iodides and active aryl bromide, such as those reported by Larhed *et al* in [bmim][PF6] (Scheme 32).[111] Using 4 mol % PdCl2 (4 mol %), P(*o*-tolyl)3 as the added Pd-ligand, reactions were complete after 5-45 min, at 180 – 220 ºC. The catalyst system and RTIL were and the time 20 minutes and 45 minutes for trans formations without the phosphine ligand. This system was recyclable at least five times, and the volatile product was

More complex Pd-catalysis such as Herman's palladacycle, *trans*-di(μ-acetato)bis[*o*-di-*o*-tolylphosphanyl) benzyl]dipalladium, have been developed in efforts to enhance Pd-coupling outcomes with unreactive aryl chlorides.[112] Using this Pd-catalyst (1.5 – 10 mol %), Heck coupling in [bmim][PF6] / dioxane mixtures with aryl chlorides and butyl acrylate gave the desired cinnamic esters.[113] High levels of phosphine ligand (3-20 %) were required dependent on the

Microwave irradiation of [omim][BF4] with 3-5 mol % Pd/C proved effective in the phosphine free Heck coupling of aryl

Bu)3PH][BF4], Cy2NMe, [bmim][PF6]/dioxane, W, 180 ºC, 30-60 min.

reactivity of the aryl chloride. Under microwave irradiation the yields were moderate to excellent (Scheme 33).[114]

**3.4. Microwave synthesis approaches** 

[115]

46 Ionic Liquids - Current State of the Art

Under conventional heating for 24 h, the Heck coupling of iodobenzene with ethyl acrylate in 1-(2-cyanoethyl)-3-(2 many advantages including: 1) highly efficient material mixing; 2) high volume to area ratio; 3) efficient heat transfers ability; 4) the avoidance of "hot spots" by effective temperature control and mixing; and 5) high operational safety.[119] The transition metal catalysed reactions have been reported by using a micro flow system, such as hydrogenation[120] and oxidation,[121] and the Heck reaction.[122] RTILs present a challenge for flow chemistry approaches due to their often-high viscosity. Ryu has examined the use of a low viscosity RTIL, [bmim]NTf2 as well as a high viscosity RTIL, [bmim][PF6].[122] The Heck coupling of iodobenzene with butyl acrylate was sluggish in [bmim][PF6], but the use of [bmim][NTf2] in a CPC CYTOS lab system gave 10 g.h-1 Micro reactor technology has and a significant impact on the chemical synthesis and produc‐ tion. This technology has many advantages including: 1) highly efficient material mixing; 2) high volume to area ratio; 3) efficient heat transfers ability; 4) the avoidance of "hot spots" by effective temperature control and mixing; and 5) high operational safety.[119] The transition metal catalysed reactions have been reported by using a micro flow system, such as hydroge‐ nation[120] and oxidation,[121] and the Heck reaction.[122] **3.5. Flow chemistry approaches**  Micro reactor technology has and a significant impact on the chemical synthesis and production. This technology has many advantages including: 1) highly efficient material mixing; 2) high volume to area ratio; 3) efficient heat transfers ability; 4) the avoidance of "hot spots" by effective temperature control and mixing; and 5) high operational safety.[119] The transition metal catalysed reactions have been reported by using a micro flow system, such as hydrogenation[120] and

hydroxyethyl)-1*H*-imidazol-3-ium tetrafluoroborate, afforded a modest 25% yield of ethyl cinnamate with PdCl2. Using microwave irradiation (200 W, 120 ºC), the same reaction system gave 88% yields of ethyl cinnamate in 5 min (Scheme 35). The system showed good stability and maintained the efficiency after six consecutive runs without significant loss of of, and in a single run with catalyst recycling, 115.3g of buyl cinnamate (Scheme 38).[123] RTILs present a challenge for flow chemistry approaches due to their often-high viscosity. Ryu has examined the use of a low viscosity RTIL, [bmim]NTf2 as well as a high viscosity RTIL, [bmim][PF6].[122] The Heck coupling of iodobenzene with butyl acrylate was sluggish in [bmim][PF6], but the use of [bmim][NTf2] in a CPC CYTOS lab system gave 10 g.h-1 of, and in a single run with catalyst recycling, 115.3g of buyl cinnamate (Scheme 38).[123] oxidation,[121] and the Heck reaction.[122] RTILs present a challenge for flow chemistry approaches due to their often-high viscosity. Ryu has examined the use of a low viscosity RTIL, [bmim]NTf2 as well as a high viscosity RTIL, [bmim][PF6].[122] The Heck coupling of iodobenzene with butyl acrylate was sluggish in [bmim][PF6], but the use of [bmim][NTf2] in a CPC CYTOS lab system gave 10 g.h-1

investigations. Active research in this area is still required to increase the scope of Heck reaction in ILs to involve more Sheme 38. Reagents and conditions: 0.1-0.5 mL.h-1, [BMIM]NTf2, 130-150 ºC, 10-50 min residence time. **Sheme 38.** Reagents and conditions: 0.1-0.5 mL.h-1, [BMIM]NTf2, 130-150 °C, 10-50 min residence time.

complicated substrates and larger scale.

**4. Conclusions** 

#### **4. Conclusions**

This approach has been extended to the palladium-catalysed Heck reactions as a key synthetic protocol for C-C bond formation. Factors affecting this approach including the type of ionic liquid used, the base and the catalyst have been investigated by many research groups. In addition, limited number of microwave-based and flow chemistry based Heck reactions have been reported. Despite these efforts, only simple aryl halides and olefines were used in the reported investigations. Active research in this area is still required to increase the scope of Heck reaction in ILs to involve more complicated substrates and larger scale. In the last twenty years has shown an increasing interest in applying ionic liquids as green solvents in organic synthesis. This approach has been extended to the palladium-catalysed Heck reactions as a key synthetic protocol for C-C bond formation. Factors affecting this approach including the type of ionic liquid used, the base and the catalyst have been investi‐ gated by many research groups. In addition, limited number of microwave-based and flow chemistry based Heck reactions have been reported. Despite these efforts, only simple aryl halides and olefines were used in the reported investigations. Active research in this area is still required to increase the scope of Heck reaction in ILs to involve more complicated substrates and larger scale.

#### **Author details**

Ahmed Al Otaibi1 , Christopher P. Gordon2 and Adam McCluskey1\*

\*Address all correspondence to: Adam.McCluskey@newcastle.edu.au

1 Chemistry, School of Environmental & Life Sciences, The University of Newcastle, Univer‐ sity Drive, Callaghan NSW, Australia

2 School of Science and Health, University of Western Sydney, Australia

#### **References**


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**Author details**

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Ahmed Al Otaibi1

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