**1. Introduction**

Catalysis by means of transition metal complexes is now a well-established tool for the organic chemist, and the continued interest in the field has led to increasingly more effective and efficient systems for carrying out a wide range of reactions, both on a laboratory and on an industrial scale. The benefits of transition metal catalysis are that the reactions are often very clean and have very high turnovers, meaning that waste products are kept to a minimum, which is one of the precepts of Green Chemistry. In addition, improvements in catalyst design are continually being made and thus allow the use of milder conditions, immobilisation on solid supports, biphasic systems for ease of separation, more benign solvents, etc. Research in the area of transition metal catalysed carbon–carbon and carbon–heteroatom coupling reactions has led to a wide variety of very efficient and useful procedures which are now most often known by the names of the scientists who pioneered their use such as Suzuki–Miyaura, Mizoroki–Heck, Negishi, Sonogashira, Kumada–Tamao–Corriu, Migita–Kosugi–Stille, Tsuji–Trost, Buchwald–Hartwig [1–9]. These procedures are mainly based on palladium although other metals have been shown to be effective in a number of cases. Phosphane ligands have traditionally been the ligands of choice for transition metal catalysis and particularly so for coupling reactions. Such systems are generally rather stable and have been refined to a very great extent. However, since phosphanes can often be water- and air-sensitive, a number of efforts have been made to develop catalysts which avoid them and instead τo employ ligands with C, N, O, or S donor groups [10], e.g., *N*-heterocyclic carbenes, carbocyclic carbenes, oxazolines, Schiff bases, amines, imidazoles, hydrazones, semicarbazones, thiosemicarbazones, thioureas, amidates, and so on. This review focuses on complexes of thiosemicarbazones and on how they can play a role in these developments.

The use of thiosemicarbazones, as well as other closely related chalcogen compounds, as ligands in metal complexes has proved to be a fruitful field of study for many years but initial reports on their application in catalysis did not appear until the 1990's [11–14], while their use in coupling

reactions was only first reported several years later [15,16]. One of the primary motivations for research into these complexes has been the various areas in which they have been proposed for application. For example, apart from their activity as catalysts, which will be covered in more detail in this review, many thiosemicarbazone metal complexes have been widely studied as potential treatments for various types of cancer, for viral, bacterial, or fungal infections, and for neurodegenerative diseases, or for malaria [17–26]. Thiosemicarbazone metal complexes have also found potential application in medical imaging [27,28], while thiosemicarbazones themselves show promise as metal ion sensors and for the scavenging of metals due to their selective and specific coordination properties [28–34]. Although related compounds such as isothiosemicarbazones, dithiocarbazates, and selenosemicarbazones have so far found less application in the catalysis of coupling reactions and will not feature in this review, it is appropriate to mention that a number of metal complexes have nevertheless been reported and that they too have been studied in areas such as oxidation processes [35–37], cytotoxicity [38–47], antimicrobials [48], imaging [49,50], and antioxidants [43,51,52]. was only first reported several years later [15,16]. One of the primary motivations for research into these complexes has been the various areas in which they have been proposed for application. For example, apart from their activity as catalysts, which will be covered in more detail in this review, many thiosemicarbazone metal complexes have been widely studied as potential treatments for various types of cancer, for viral, bacterial, or fungal infections, and for neurodegenerative diseases, or for malaria [17–26]. Thiosemicarbazone metal complexes have also found potential application in medical imaging [27,28], while thiosemicarbazones themselves show promise as metal ion sensors and for the scavenging of metals due to their selective and specific coordination properties [28–34]. Although related compounds such as isothiosemicarbazones, dithiocarbazates, and selenosemicarbazones have so far found less application in the catalysis of coupling reactions and will not feature in this review, it is appropriate to mention that a number of metal complexes have nevertheless been reported and that they too have been studied in areas such as oxidation processes [35–37], cytotoxicity [38–47], antimicrobials [48], imaging [49,50], and antioxidants [43,51,52]. was only first reported several years later [15,16]. One of the primary motivations for research into these complexes has been the various areas in which they have been proposed for application. For example, apart from their activity as catalysts, which will be covered in more detail in this review, many thiosemicarbazone metal complexes have been widely studied as potential treatments for various types of cancer, for viral, bacterial, or fungal infections, and for neurodegenerative diseases, or for malaria [17–26]. Thiosemicarbazone metal complexes have also found potential application in medical imaging [27,28], while thiosemicarbazones themselves show promise as metal ion sensors and for the scavenging of metals due to their selective and specific coordination properties [28–34]. Although related compounds such as isothiosemicarbazones, dithiocarbazates, and selenosemicarbazones have so far found less application in the catalysis of coupling reactions and will not feature in this review, it is appropriate to mention that a number of metal complexes have nevertheless been reported and that they too have been studied in areas such as oxidation processes [35–37], cytotoxicity [38–47], antimicrobials [48], imaging [49,50], and antioxidants [43,51,52].

application in catalysis did not appear until the 1990's [11–14], while their use in coupling reactions

application in catalysis did not appear until the 1990's [11–14], while their use in coupling reactions

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Another important aspect of thiosemicarbazones as ligands is the wide variety of coordination modes which can be adopted. Numerous structural studies have been carried out and this area has been the subject of a number of reviews [17,53–55]. An equilibrium mixture of thione (**I**) and thiol (**II**) tautomers exists in solution (Scheme 1). The simplest thiosemicarbazones, without any additional potential donor sites, can adopt a bidentate configuration either in their neutral form or in their deprotonated form as an anionic ligand. Many thiosemicarbazones, however, also have additional functionality which provides further potential donor sites and thus enables tridentate or higher degrees of denticity (Scheme 2). This becomes important when dealing with carbon–carbon coupling reactions, and especially those involving palladium complexes, since pincer-type Pd(II) complexes are known to efficiently catalyse carbon–carbon coupling reactions [56], and it has been hypothesised that the tridentate coordination of the pincer ligand stabilises the metal–carbon bond during the catalytic cycle [57]. Another important aspect of thiosemicarbazones as ligands is the wide variety of coordination modes which can be adopted. Numerous structural studies have been carried out and this area has been the subject of a number of reviews [17,53–55]. An equilibrium mixture of thione **(I)** and thiol **(II)** tautomers exists in solution (Scheme 1). The simplest thiosemicarbazones, without any additional potential donor sites, can adopt a bidentate configuration either in their neutral form or in their deprotonated form as an anionic ligand. Many thiosemicarbazones, however, also have additional functionality which provides further potential donor sites and thus enables tridentate or higher degrees of denticity (Scheme 2). This becomes important when dealing with carbon–carbon coupling reactions, and especially those involving palladium complexes, since pincer-type Pd(II) complexes are known to efficiently catalyse carbon–carbon coupling reactions [56], and it has been hypothesised that the tridentate coordination of the pincer ligand stabilises the metal–carbon bond during the catalytic cycle [57]. Another important aspect of thiosemicarbazones as ligands is the wide variety of coordination modes which can be adopted. Numerous structural studies have been carried out and this area has been the subject of a number of reviews [17,53–55]. An equilibrium mixture of thione **(I)** and thiol **(II)** tautomers exists in solution (Scheme 1). The simplest thiosemicarbazones, without any additional potential donor sites, can adopt a bidentate configuration either in their neutral form or in their deprotonated form as an anionic ligand. Many thiosemicarbazones, however, also have additional functionality which provides further potential donor sites and thus enables tridentate or higher degrees of denticity (Scheme 2). This becomes important when dealing with carbon–carbon coupling reactions, and especially those involving palladium complexes, since pincer-type Pd(II) complexes are known to efficiently catalyse carbon–carbon coupling reactions [56], and it has been hypothesised that the tridentate coordination of the pincer ligand stabilises the metal–carbon bond during the catalytic cycle [57].

$$\begin{array}{c} \mathsf{R}^{2}\_{\mathsf{A}^{2}\_{\mathsf{i}}} \mathsf{c} = \mathsf{N} - \mathsf{N} - \mathsf{C} - \mathsf{N} \\ \mathsf{R}^{2}\_{\mathsf{i}} \mathsf{c} = \mathsf{N} - \mathsf{N} - \mathsf{N} \\ \mathsf{I} \\ \end{array} \xleftarrow{\mathsf{R}^{3}} \xleftarrow{\mathsf{R}^{3}} \xleftarrow{\mathsf{R}^{4}} \mathsf{C} = \mathsf{N} - \mathsf{N} = \mathsf{C} - \mathsf{N} \Big\prime\_{\mathsf{A}^{2}} \mathsf{R}^{2}\_{\mathsf{i}} \mathsf{c} $$

**Scheme 1.** Tautomerism of thiosemicarbazones. **Scheme 1.** Tautomerism of thiosemicarbazones. **Scheme 1.** Tautomerism of thiosemicarbazones.

**Scheme 2.** Representative coordination modes of thiosemicarbazones. **Scheme 2.** Representative coordination modes of thiosemicarbazones.

**Scheme 2.** Representative coordination modes of thiosemicarbazones. This versatility of coordination, together with the relative ease with which these ligands can often be prepared, has provided a considerable impetus into the study of their metal complexes, and particularly how it can be exploited for the development of new catalysts. Reactions which have been studied using these systems include oxidation [58–74], transfer hydrogenation [75–77], reduction [14], silane alcoholysis [12,13,78], condensation reactions [79–81], and the cyclopropanation of olefins [82,83], as well as coupling reactions which are described here. Some of these have also previously been covered by Kumar et al*.* in reviews of the role of organochalcogen ligands in Mizoroki–Heck This versatility of coordination, together with the relative ease with which these ligands can often be prepared, has provided a considerable impetus into the study of their metal complexes, and particularly how it can be exploited for the development of new catalysts. Reactions which have been studied using these systems include oxidation [58–74], transfer hydrogenation [75–77], reduction [14], silane alcoholysis [12,13,78], condensation reactions [79–81], and the cyclopropanation of olefins [82,83], as well as coupling reactions which are described here. Some of these have also previously been covered by Kumar et al*.* in reviews of the role of organochalcogen ligands in Mizoroki–Heck This versatility of coordination, together with the relative ease with which these ligands can often be prepared, has provided a considerable impetus into the study of their metal complexes, and particularly how it can be exploited for the development of new catalysts. Reactions which have been studied using these systems include oxidation [58–74], transfer hydrogenation [75–77], reduction [14], silane alcoholysis [12,13,78], condensation reactions [79–81], and the cyclo propanation of olefins [82,83], as well as coupling reactions which are described here. Some of these have also previously been covered by Kumar et al. in reviews of the role of organochalcogen ligands in Mizoroki–Heck and Suzuki–Miyaura reactions [84–86]. The present review is organised according to

the nature of the bond formed, i.e. carbon–carbon or carbon–heteroatom, with further subdivisions within these categories. It should be noted that, as with many other catalytic systems, the complexes used should usually more accurately be referred to as pre-catalysts since the active species are often formed in the reaction system. Indeed, there may be more than one active species formed, giving rise to a catalytic "cocktail" [87,88]. There have been numerous studies concerning the mechanism of coupling reactions catalysed by transition metal complexes which discuss the nature and formation of these cocktails as well as other related features of these reactions such as the aggregation of complexes or their de-aggregation, leaching effects, the role of nanoparticles and so on [89–92] but relatively little such work has been done, however, on thiosemicarbazone complexes. This aspect is therefore very much in its infancy and the present review will attempt to highlight the most significant studies in this area. the bond formed, i.e. carbon–carbon or carbon–heteroatom, with further subdivisions within these categories. It should be noted that, as with many other catalytic systems, the complexes used should usually more accurately be referred to as pre-catalysts since the active species are often formed in the reaction system. Indeed, there may be more than one active species formed, giving rise to a catalytic "cocktail" [87,88]. There have been numerous studies concerning the mechanism of coupling reactions catalysed by transition metal complexes which discuss the nature and formation of these cocktails as well as other related features of these reactions such as the aggregation of complexes or their de-aggregation, leaching effects, the role of nanoparticles and so on [89–92] but relatively little such work has been done, however, on thiosemicarbazone complexes. This aspect is therefore very much in its infancy and the present review will attempt to highlight the most significant studies in this area.

and Suzuki–Miyaura reactions [84–86]. The present review is organised according to the nature of

#### **2. Carbon–Carbon Coupling Reactions 2. Carbon–Carbon Coupling Reactions**

#### *2.1. Mizoroki–Heck Reaction 2.1. Mizoroki–Heck Reaction*

The palladium catalysed coupling of alkenes and aryl halides was discovered independently by Mizoroki and Heck (Scheme 3). The numerous modifications and variations of this reaction have been so extensively reviewed that there is even a review of reviews on the subject [93]. Metal complexes of thiosemicarbazones that have been used as catalysts for this reaction are shown in Figure 1. The palladium catalysed coupling of alkenes and aryl halides was discovered independently by Mizoroki and Heck (Scheme 3). The numerous modifications and variations of this reaction have been so extensively reviewed that there is even a review of reviews on the subject [93]. Metal complexes of thiosemicarbazones that have been used as catalysts for this reaction are shown in Figure 1.

**Scheme 3.** Mizoroki–Heck reaction. **Scheme 3.** Mizoroki–Heck reaction.

The first reported use of a thiosemicarbazone in the Heck reaction was in 2004 by the groups of Kovala-Demertzi and Kostas using a palladium complex of salicylaldehyde *N*(4)-ethylthiosemicarbazone (**1a**) (Figure 1) [15]. The crystal structure of the complex indicated that the ligand behaved as a tridentate ligand with N, S and O bonded to the metal. The reaction of styrene with a range of aryl bromides in the presence of varying concentrations of the complex was carried out in DMF (dimethylformamide) at 150 °C both in air and also under an argon atmosphere (Scheme 4). It was found that, as is normally the case for the Heck reaction, the catalytic activity was greater for aryl bromides with electron-withdrawing groups and decreased in the order NO<sup>2</sup> > CHO > H > OMe, leading to the conclusion that the oxidative addition of the aryl bromide to the complex was the ratedetermining step. The use of an inert atmosphere in general gave better results, particularly for the least active aryl bromides and for low catalyst concentrations. However, the complex was stable enough in air under the reaction conditions to catalyse the reaction for the more activated aryl bromides, and turnover numbers (TONs) ranging from 120 to 14,000 and turnover frequencies (TOFs) in the range 5–583 h–<sup>1</sup> were found. Using similar systems, **2**, involving derivatives of salicylaldehydethiosemicarbazone with an additional PPh3 ligand, Xie et al*.* studied the catalysis of the Heck reaction of iodobenzene with methyl acrylate [94]. Having found that the methoxyderivative **2c** gave the best yields in initial experiments, they examined the reaction with a range of other aryl iodides and aryl bromides, and with different solvents and bases. Generally, good to very good yields were obtained using aryl iodides and various acrylate esters under an argon atmosphere with DMF as solvent, K2CO<sup>3</sup> as base, a temperature of 110–130 °C and a catalyst loading of at least 0.01 mol%. Using Na2CO3, lower catalyst loading also gave good results and this base was used in The first reported use of a thiosemicarbazone in the Heck reaction was in 2004 by the groups of Kovala-Demertzi and Kostas using a palladium complex of salicylaldehyde *N*(4)-ethylthiosemi carbazone (**1a**) (Figure 1) [15]. The crystal structure of the complex indicated that the ligand behaved as a tridentate ligand with N, S and O bonded to the metal. The reaction of styrene with a range of aryl bromides in the presence of varying concentrations of the complex was carried out in DMF (dimethylformamide) at 150 ◦C both in air and also under an argon atmosphere (Scheme 4). It was found that, as is normally the case for the Heck reaction, the catalytic activity was greater for aryl bromides with electron-withdrawing groups and decreased in the order NO<sup>2</sup> > CHO > H > OMe, leading to the conclusion that the oxidative addition of the aryl bromide to the complex was the rate-determining step. The use of an inert atmosphere in general gave better results, particularly for the least active aryl bromides and for low catalyst concentrations. However, the complex was stable enough in air under the reaction conditions to catalyse the reaction for the more activated aryl bromides, and turnover numbers (TONs) ranging from 120 to 14,000 and turnover frequencies (TOFs) in the range 5–583 h–1 were found. Using similar systems, **2**, involving derivatives of salicylaldehydethiosemicarbazone with an additional PPh<sup>3</sup> ligand, Xie et al. studied the catalysis of the Heck reaction of iodobenzene with methyl acrylate [94]. Having found that the methoxy-derivative **2c** gave the best yields in initial experiments, they examined the reaction with a range of other aryl iodides and aryl bromides, and with different solvents and bases. Generally, good to very good yields were obtained using aryl iodides and various acrylate esters under an argon atmosphere with DMF as solvent, K2CO<sup>3</sup> as base, a temperature of 110–130 ◦C and a catalyst loading of at least 0.01 mol%. Using Na2CO3, lower catalyst loading also gave good results and this base was used in the reactions of the aryl bromides (Scheme 5). In the latter

case, catalyst loadings of 0.1 or 1 mol% were necessary in order to obtain acceptable yields. Bidentate thiosemicarbazone complexes of palladium were investigated as catalysts in coupling reactions by Paul et al. [95]. They found that, in the Heck reaction, the complexes **3** and **4** displayed catalytic behavior at 0.5 mol% catalyst loading for the reaction between some aryl bromides and *n*-butyl acrylate (Scheme 6). The authors used Cs2CO<sup>3</sup> as base and either ethanol-toluene or PEG (polyethylene glycol) as solvent at 110–150 ◦C. Although the results were only moderately good, this system could have much room for optimization taking into account the observation of Xie et al. (see above) that PEG was a poor solvent for the similar system that they examined and that K2CO<sup>3</sup> was a superior base than Cs2CO3. the reactions of the aryl bromides (Scheme 5). In the latter case, catalyst loadings of 0.1 or 1 mol% were necessary in order to obtain acceptable yields. Bidentate thiosemicarbazone complexes of palladium were investigated as catalysts in coupling reactions by Paul et al*.* [95]. They found that, in the Heck reaction, the complexes **3** and **4** displayed catalytic behavior at 0.5 mol% catalyst loading for the reaction between some aryl bromides and *n*-butyl acrylate (Scheme 6). The authors used Cs2CO<sup>3</sup> as base and either ethanol-toluene or PEG (polyethylene glycol) as solvent at 110–150 °C. Although the results were only moderately good, this system could have much room for optimization taking into account the observation of Xie et al*.* (see above) that PEG was a poor solvent for the similar system that they examined and that K2CO<sup>3</sup> was a superior base than Cs2CO3. for the reaction between some aryl bromides and *n*-butyl acrylate (Scheme 6). The authors used Cs2CO<sup>3</sup> as base and either ethanol-toluene or PEG (polyethylene glycol) as solvent at 110–150 °C. Although the results were only moderately good, this system could have much room for optimization taking into account the observation of Xie et al*.* (see above) that PEG was a poor solvent for the similar system that they examined and that K2CO<sup>3</sup> was a superior base than Cs2CO3.

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the Heck reaction, the complexes **3** and **4** displayed catalytic behavior at 0.5 mol% catalyst loading

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the reactions of the aryl bromides (Scheme 5). In the latter case, catalyst loadings of 0.1 or 1 mol%

**Figure 1.** Representative metal complexes of thiosemicarbazones as catalysts for the Mizoroki–Heck and other coupling reactions. **Figure 1.** Representative metal complexes of thiosemicarbazones as catalysts for the Mizoroki–Heck and other coupling reactions. **Figure 1.** Representative metal complexes of thiosemicarbazones as catalysts for the Mizoroki–Heck and other coupling reactions.

**Scheme 4.** Heck reaction of aryl bromides with styrene catalysed by complex **1a**: The first reported use of a thiosemicarbazone in the Heck reaction.

use of a thiosemicarbazone in the Heck reaction.

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**Scheme 4.** Heck reaction of aryl bromides with styrene catalysed by complex **1a**: The first reported

**Scheme 4.** Heck reaction of aryl bromides with styrene catalysed by complex **1a**: The first reported

**Scheme 5.** Heck reaction of aryl bromides with methyl acrylate catalysed by complex **2c**. **Scheme 5.** Heck reaction of aryl bromides with methyl acrylate catalysed by complex **2c**. **Scheme 5.** Heck reaction of aryl bromides with methyl acrylate catalysed by complex **2c**. **Scheme 5.** Heck reaction of aryl bromides with methyl acrylate catalysed by complex **2c**.

**Scheme 6.** Heck reaction of aryl bromides and *n*-butyl acrylate catalysed by complexes **3** or **4**. **Scheme 6.** Heck reaction of aryl bromides and *n*-butyl acrylate catalysed by complexes **3** or **4**. **Scheme 6.** Heck reaction of aryl bromides and *n*-butyl acrylate catalysed by complexes **3**or **4**.

**Scheme 6.** Heck reaction of aryl bromides and *n*-butyl acrylate catalysed by complexes **3** or **4**. The dinuclear bis-bidentate palladium complex **5**, which also possesses PPh<sup>3</sup> ligands coordinated to the metal, was prepared and structurally characterized by Prabhu and Ramesh who subsequently made a systematic study of its catalytic activity in the Heck reaction of *p*-bromoacetophenone with *t*butyl acrylate, examining the effect of temperature, solvent, base and catalyst loading [96]. Inorganic bases such as K2CO<sup>3</sup> or Na2CO<sup>3</sup> were superior to amines, DMF was the optimal solvent and a temperature of 100 °C provided the best results within a reasonable time. Catalyst loadings of 1 or 0.1 mol% gave quantitative yields but it is worth noting that the reaction proceeds even at very low catalyst loading of 0.00001 mol%, and, although the yield in this case is low (11%), the turnover number (1,100,000) and the turnover frequency (137,500 h–<sup>1</sup> ) are still impressive. Using optimized conditions, the authors were able to demonstrate the activity of the complex for a wide range of electron-withdrawing and electron-donating aryl bromides with methyl and *t*-butyl acrylate, styrene, *p*-methylstyrene, and *p*-chlorostyrene (Scheme 7). TONs of 6,000 to 9,800 and TOFs in the range 750– The dinuclear bis-bidentate palladium complex **5**, which also possesses PPh<sup>3</sup> ligands coordinated to the metal, was prepared and structurally characterized by Prabhu and Ramesh who subsequently made a systematic study of its catalytic activity in the Heck reaction of *p*-bromoacetophenone with *t*butyl acrylate, examining the effect of temperature, solvent, base and catalyst loading [96]. Inorganic bases such as K2CO<sup>3</sup> or Na2CO<sup>3</sup> were superior to amines, DMF was the optimal solvent and a temperature of 100 °C provided the best results within a reasonable time. Catalyst loadings of 1 or 0.1 mol% gave quantitative yields but it is worth noting that the reaction proceeds even at very low catalyst loading of 0.00001 mol%, and, although the yield in this case is low (11%), the turnover number (1,100,000) and the turnover frequency (137,500 h–<sup>1</sup> ) are still impressive. Using optimized conditions, the authors were able to demonstrate the activity of the complex for a wide range of electron-withdrawing and electron-donating aryl bromides with methyl and *t*-butyl acrylate, styrene, *p*-methylstyrene, and *p*-chlorostyrene (Scheme 7). TONs of 6,000 to 9,800 and TOFs in the range 750– 1225 h–<sup>1</sup> were reported. The dinuclear bis-bidentate palladium complex **5**, which also possesses PPh<sup>3</sup> ligands coordinated to the metal, was prepared and structurally characterized by Prabhu and Ramesh who subsequently made a systematic study of its catalytic activity in the Heck reaction of *p*-bromoacetophenone with *t*-butyl acrylate, examining the effect of temperature, solvent, base and catalyst loading [96]. Inorganic bases such as K2CO<sup>3</sup> or Na2CO<sup>3</sup> were superior to amines, DMF was the optimal solvent and a temperature of 100 ◦C provided the best results within a reasonable time. Catalyst loadings of 1 or 0.1 mol% gave quantitative yields but it is worth noting that the reaction proceeds even at very low catalyst loading of 0.00001 mol%, and, although the yield in this case is low (11%), the turnover number (1,100,000) and the turnover frequency (137,500 h–1) are still impressive. Using optimized conditions, the authors were able to demonstrate the activity of the complex for a wide range of electron-withdrawing and electron-donating aryl bromides with methyl and *t*-butyl acrylate, styrene, *p*-methylstyrene, and *p*-chlorostyrene (Scheme 7). TONs of 6,000 to 9,800 and TOFs in the range 750–1225 h–1 were reported. The dinuclear bis-bidentate palladium complex **5**, which also possesses PPh3ligands coordinated to the metal, was prepared and structurally characterized by Prabhu and Ramesh who subsequently made a systematic study of its catalytic activity in the Heck reaction of *p*-bromoacetophenone with *t*butyl acrylate, examining the effect of temperature, solvent, base and catalyst loading [96]. Inorganic bases such as K2CO<sup>3</sup> or Na2CO<sup>3</sup> were superior to amines, DMF was the optimal solvent and a temperature of 100 °C provided the best results within a reasonable time. Catalyst loadings of 1 or 0.1 mol% gave quantitative yields but it is worth noting that the reaction proceeds even at very low catalyst loading of 0.00001 mol%, and, although the yield in this case is low (11%), the turnover number (1,100,000) and the turnover frequency (137,500 h–<sup>1</sup> ) are still impressive. Using optimized conditions, the authors were able to demonstrate the activity of the complex for a wide range of electron-withdrawing and electron-donating aryl bromides with methyl and *t*-butyl acrylate, styrene, *p*-methylstyrene, and *p*-chlorostyrene (Scheme 7). TONs of 6,000 to 9,800 and TOFs in the range 750– 1225 h–<sup>1</sup> were reported.

**Scheme 7.** Heck reaction of aryl bromides with acrylate esters or substituted styrenes catalysed by **Scheme 7.** Heck reaction of aryl bromides with acrylate esters or substituted styrenes catalysed by complex **5**. **Scheme 7.** Heck reaction of aryl bromides with acrylate esters or substituted styrenes catalysed by complex **5**. **Scheme 7.** Heck reaction of aryl bromides with acrylate esters or substituted styrenes catalysed by complex **5**.

complex **5**. The above studies all involved complexes of palladium but there have also been reports of the application of thiosemicarbazone nickel complexes to coupling reactions. One of the main motivations for this is the relatively low cost of nickel compared with palladium while, on the other hand, the main difficulty that needs to be surmounted is the well-established high efficiency of palladium complexes. It is also conceivable that there are important mechanistic differences in the mode of action of the complexes of the two metals but, for thiosemicarbazone complexes at least, no systematic studies have yet been carried out. The first report of the application of thiosemicarbazone The above studies all involved complexes of palladium but there have also been reports of the application of thiosemicarbazone nickel complexes to coupling reactions. One of the main motivations for this is the relatively low cost of nickel compared with palladium while, on the other hand, the main difficulty that needs to be surmounted is the well-established high efficiency of palladium complexes. It is also conceivable that there are important mechanistic differences in the mode of action of the complexes of the two metals but, for thiosemicarbazone complexes at least, no systematic studies have yet been carried out. The first report of the application of thiosemicarbazone The above studies all involved complexes of palladium but there have also been reports of the application of thiosemicarbazone nickel complexes to coupling reactions. One of the main motivations for this is the relatively low cost of nickel compared with palladium while, on the other hand, the main difficulty that needs to be surmounted is the well-established high efficiency of palladium complexes. It is also conceivable that there are important mechanistic differences in the mode of action of the complexes of the two metals but, for thiosemicarbazone complexes at least, no systematic studies have yet been carried out. The first report of the application of thiosemicarbazone The above studies all involved complexes of palladium but there have also been reports of the application of thiosemicarbazone nickel complexes to coupling reactions. One of the main motivations for this is the relatively low cost of nickel compared with palladium while, on the other hand, the main difficulty that needs to be surmounted is the well-established high efficiency of palladium complexes. It is also conceivable that there are important mechanistic differences in the mode of action of the complexes of the two metals but, for thiosemicarbazone complexes at least, no systematic studies have yet been carried out. The first report of the application of thiosemicarbazone nickel complexes to the Heck reaction was by Datta et al., who prepared and characterized three complexes with 2-hydroxyaryl thiosemicarbazone ligands [97]. Dinuclear complexes with tridentate *N*,*S*,*O*-coordination were formed which were reacted with PPh3, pyridine, or bipyridine to give mononuclear complexes that retained

the tridentate coordination. The complexes were examined for their catalytic efficiency in the reaction of *p*-bromoacetophenone, *p*-bromobenzonitrile, and *p*-bromobenzaldehyde with butyl acrylate in DMF at 130 ◦C. Catalyst loadings of 2 mol% were found to give good yields but TONs (18–50) and TOFs (2.1 <sup>×</sup> <sup>10</sup>–4 sec–1) were modest compared with TONs of analogous palladium complexes (8000). One encouraging feature, however, was that coupling reactions of aryl chlorides also proceeded with yields of a similar order of magnitude to the more reactive aryl bromides and iodides. Better results, at least as far as aryl bromides are concerned, were obtained using the nickel complex **6** reported by Suganthy et al. [98]. Using optimized conditions, this bis(thiosemicarbazone) nickel complex catalysed the reaction between a series of aryl bromides and methyl and *t*-butylacrylate, styrene, *p*-methylstyrene and *p*-chlorostyrene (Scheme 8). Using catalyst loadings of 0.5 mol%, moderate to very good conversions were obtained with turnover numbers ranging from 120 to 188 and turnover frequencies in the range 5–8 h–1. However, it is significant that, compared with the system mentioned above [97], no catalytic activity was observed in the coupling of 4-chloroacetophenone with *t*-butyl acrylate in DMF/K2CO<sup>3</sup> even after 24 h at elevated temperatures. mononuclear complexes that retained the tridentate coordination. The complexes were examined for their catalytic efficiency in the reaction of *p*-bromoacetophenone, *p*-bromobenzonitrile, and *p*bromobenzaldehyde with butyl acrylate in DMF at 130 °C. Catalyst loadings of 2 mol% were found to give good yields but TONs (18–50) and TOFs (2.1 × 10–<sup>4</sup> sec–<sup>1</sup> ) were modest compared with TONs of analogous palladium complexes (8000). One encouraging feature, however, was that coupling reactions of aryl chlorides also proceeded with yields of a similar order of magnitude to the more reactive aryl bromides and iodides. Better results, at least as far as aryl bromides are concerned, were obtained using the nickel complex **6** reported by Suganthy et al*.* [98]. Using optimized conditions, this bis(thiosemicarbazone) nickel complex catalysed the reaction between a series of aryl bromides and methyl and *t*-butylacrylate, styrene, *p*-methylstyrene and *p*-chlorostyrene (Scheme 8). Using catalyst loadings of 0.5 mol%, moderate to very good conversions were obtained with turnover numbers ranging from 120 to 188 and turnover frequencies in the range 5–8 h–<sup>1</sup> . However, it is significant that, compared with the system mentioned above [97], no catalytic activity was observed in the coupling of 4-chloroacetophenone with *t*-butyl acrylate in DMF/K2CO<sup>3</sup> even after 24 h at elevated temperatures.

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 6 of 42

nickel complexes to the Heck reaction was by Datta et al*.*, who prepared and characterized three

*N*,*S*,*O*-coordination were formed which were reacted with PPh3, pyridine, or bipyridine to give

**Scheme 8.** Heck reaction of aryl bromides with acrylate esters or substituted styrenes catalysed by Ni complex **6**. **Scheme 8.** Heck reaction of aryl bromides with acrylate esters or substituted styrenes catalysed by Ni complex **6**.

Very recently, a comparative study has been made of similar thiosemicarbazone complexes of nickel, palladium, and platinum [99]. Using a tetradentate bis-thiosemicarbazone ligand, Lima et al*.* synthesized the complexes **7**. The tetradentate coordination was verified by X-ray diffraction structural determinations and the complexes were subsequently studied in the Heck reaction of iodobenzene with styrene. The palladium complex was an active catalyst at loadings of 3.5 mol% or above in a reaction carried out in DMF at 120 °C using triethylamine as the base. The platinum and nickel complexes showed activity but much less than the Pd complex. The palladium system appears to show much less catalytic activity than previously reported complexes and this may be due to the lack of free coordination sites in the tetracoordinated complex. On the other hand, it should be noted that the use of an organic base instead of an inorganic one is known to play a significant role and this also should be taken into account. It is also not clear from the report whether an inert atmosphere was employed. The authors performed preliminary DFT calculations from which they postulate that the process involving the tetradentate Pd complex does not follow the typical reaction mechanism for Heck catalysts involving an initial Pd(0)-Pd(II) oxidative-addition step. The calculations indicated a partial charge of +1.154 on the metal in the palladium complex compared to a much lower charge of +0.284 on the metal in the nickel one. Taking into account the increased catalytic activity of the Pd complex, and on the basis of their calculations for the likely steps in the catalytic cycle, the authors suggest that the reaction proceeds via an initial Pd(II)-Pd(IV) oxidative-addition of the aryl halide followed by olefin insertion and reductive elimination. Very recently, a comparative study has been made of similar thiosemicarbazone complexes of nickel, palladium, and platinum [99]. Using a tetradentate bis-thiosemicarbazone ligand, Lima et al. synthesized the complexes **7**. The tetradentate coordination was verified by X-ray diffraction structural determinations and the complexes were subsequently studied in the Heck reaction of iodobenzene with styrene. The palladium complex was an active catalyst at loadings of 3.5 mol% or above in a reaction carried out in DMF at 120 ◦C using triethylamine as the base. The platinum and nickel complexes showed activity but much less than the Pd complex. The palladium system appears to show much less catalytic activity than previously reported complexes and this may be due to the lack of free coordination sites in the tetracoordinated complex. On the other hand, it should be noted that the use of an organic base instead of an inorganic one is known to play a significant role and this also should be taken into account. It is also not clear from the report whether an inert atmosphere was employed. The authors performed preliminary DFT calculations from which they postulate that the process involving the tetradentate Pd complex does not follow the typical reaction mechanism for Heck catalysts involving an initial Pd(0)-Pd(II) oxidative-addition step. The calculations indicated a partial charge of +1.154 on the metal in the palladium complex compared to a much lower charge of +0.284 on the metal in the nickel one. Taking into account the increased catalytic activity of the Pd complex, and on the basis of their calculations for the likely steps in the catalytic cycle, the authors suggest that the reaction proceeds via an initial Pd(II)-Pd(IV) oxidative-addition of the aryl halide followed by olefin insertion and reductive elimination.

Published reports of the use of thiosemicarbazone complexes as described above for the Mizoroki–Heck reaction are summarised in Table 1 for indicative reactions. Published reports of the use of thiosemicarbazone complexes as described above for the Mizoroki–Heck reaction are summarised in Table 1 for indicative reactions.


**Table 1.** Mizoroki–Heck reactions catalysed by thiosemicarbazone complexes: representative conditions and yields <sup>1</sup> .

1 conditions refer to reactions involving aryl bromides and (substituted) styrenes or acrylates. <sup>2</sup> ligand donor atoms. 3 for the reaction of PhI with styrene.
