*2.2. Suzuki–Miyaura and Related Reactions*

The coupling of alkenyl, alkynyl, and aryl halides with boronic acids and related derivatives by palladium complexes, first reported in 1979 by Miyaura and Suzuki, led to intense research activity aiming at optimising the reaction and extending its application to increasingly more demanding systems (Scheme 9). Numerous reviews have appeared and continue to appear on the subject [2,3]. Representative metal complexes of thiosemicarbazones that have been used as catalysts for this reaction are shown in Figures 2–4; see also in Figure 1.

The first report of the use of thiosemicarbazone complexes in this reaction was by Kostas et al., who studied the cross-coupling of aryl halides with phenylboronic acid (Scheme 10) [16]. The complexes **1a** and **1b** used were derived from salicylaldehyde (Figure 1), and one of them (**1a**) having already been successfully used in the Heck reaction as mentioned above [15]. The complexes are air-stable and this therefore enabled the reactions to be carried out without the need for an inert atmosphere. In addition, they are moisture-stable and in fact the addition of one equivalent of water was found to be beneficial. Aryl bromides with varying substitution were used and, as had been previously observed in reactions with other catalysts, the best results were obtained with electron-withdrawing substituents. Catalyst loadings of 0.1 mol% gave moderate to very good conversions for most substrates in reactions in DMF at 100 ◦C using Na2CO<sup>3</sup> as base, but even lower loadings of 0.001 mol% were also active systems, albeit with lower conversions. TONs ranging from 400 to 49,000 and TOFs in the range 17–2042 h–1 were reported. The reaction with aryl chlorides was also catalysed by these complexes but, as expected, with somewhat lower TONs (260–370) and TOFs (11–15 h–1). These complexes were less active than some previously reported P-systems but have the important advantage of being phosphane free and requiring less demanding conditions. In a subsequent paper, the same group reported on the synthesis and characterisation of a new palladium thiosemicarbazone complex **8** (Figure 2) [100]. The thiosemicarbazone was again derived from salicylaldehyde but with a tertiary amino end group derived from hexamethyleneimine. The crystal structure determination of the bis-ligand palladium complex demonstrated that the two ligands were coordinated in a bidentate fashion via N and S donors. In contrast with the complexes in the previous study, the oxygen on the salicylaldehyde portion was not involved in direct bonding to the metal but was connected via a hydrogen bond to the unsubstituted thioamide nitrogen. This complex did not demonstrate catalytic activity in the Suzuki–Miyaura reaction using the conditions employed in the previous work, and it was proposed that this is because the metal is bonded to two thiosemicarbazone moieties by four intramolecular bonds, resulting in inhibition of the addition of the aryl halide to the metal during the catalytic cycle. However, using microwave irradiation, positive results were obtained for the reaction of bromobenzene and *p*-nitrobromobenzene with phenylboronic acid (Scheme 11). As in the previous study, the addition of water was found to be beneficial and good yields were obtained after up to 60 min irradiation using DMF as solvent and Na2CO<sup>3</sup> as base. Catalyst loadings of 0.1 mol% were used for reactions with bromobenzene and 0.001 mol% for those with *p*-nitrobromobenzene. TONs of up to 37,000 and TOFs

9

conditions and yields <sup>1</sup>

Pd <sup>110</sup>–<sup>150</sup> EtOH/toluene

*2.2. Suzuki–Miyaura and Related Reactions*

*Catalysts* 

.

donor atoms. <sup>3</sup> for the reaction of PhI with styrene.

of up to 617 min–1 were recorded. The reaction of phenylboronic acid with *p*-nitrochlorobenzene was also successful under these conditions. The observation that conventional heating failed to promote the reaction prompted the authors to postulate that the acceleration of the reaction was due to specific microwave effects [100,101]. The coupling of alkenyl, alkynyl, and aryl halides with boronic acids and related derivatives by palladium complexes, first reported in 1979 by Miyaura and Suzuki, led to intense research activity aiming at optimising the reaction and extending its application to increasingly more demanding systems (Scheme 9). Numerous reviews have appeared and continue to appear on the subject [2,3]. Representative metal complexes of thiosemicarbazones that have been used as catalysts for this reaction are shown in Figures 2–4; see also in Figure 1.

<sup>1</sup> conditions refer to reactions involving aryl bromides and (substituted) styrenes or acrylates.

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 7 of 42 **Table 1.** Mizoroki–Heck reactions catalysed by thiosemicarbazone complexes: representative

**Metal T (°C) Solvent Time (h) Ligand <sup>2</sup> Base Catalyst (mol%) Yield (%) Ref.** Pd 150 DMF 24 O,N,S NaOAc 0.1 46–95 [15] Pd 130–145 DMF 24–36 O,N,S Na2CO<sup>3</sup> 0.1–1.0 50–90 [94]

Pd 100 DMF 8 N,S K2CO<sup>3</sup> 0.01 60–97 [96] Ni 130 DMF 24 O,N,S Cs2CO<sup>3</sup> 2.0 36–99 [97] Ni 110 DMF 24 N,S K2CO<sup>3</sup> 0.5 60–94 [98] Pd 120 DMF 5–24 S,N,N,S Et3N 3.5 67–82 <sup>3</sup> [99]

or PEG <sup>12</sup>–<sup>48</sup> N,S Cs2CO<sup>3</sup> 0.5–1.0 <sup>57</sup>–<sup>80</sup> [95]

2 ligand

**Scheme 9.** Suzuki–Miyaura reaction. **Scheme 9.** Suzuki–Miyaura reaction. **2020**, *10*, x FOR PEER REVIEW 9 of 42

**Figure 2.** Representative metal complexes of thiosemicarbazones as catalysts for the Suzuki–Miyaura and other coupling reactions (Part A). **Figure 2.** Representative metal complexes of thiosemicarbazones as catalysts for the Suzuki–Miyaura and other coupling reactions (Part A).

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 14 of 42

**Figure 3.** Representative metal complexes of thiosemicarbazones as catalysts for the Suzuki–Miyaura and other coupling reactions (Part B). **Figure 3.** Representative metal complexes of thiosemicarbazones as catalysts for the Suzuki–Miyaura and other coupling reactions (Part B).

complex **23**.

h–<sup>1</sup>

h–<sup>1</sup>

and TOF of 5,000 h–<sup>1</sup>

and TOF of 5,000 h–<sup>1</sup>

.

.

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 17 of 42

**Figure 4.** Representative metal complexes of thiosemicarbazones as catalysts for the Suzuki–Miyaura and other coupling reactions (Part C). **Figure 4.** Representative metal complexes of thiosemicarbazones as catalysts for the Suzuki–Miyaura and other coupling reactions (Part C). *Catalysts* **2020**, *10*, x FOR PEER REVIEW 10 of 42 *Catalysts* **2020**, *10*, x FOR PEER REVIEW 10 of 42

**Scheme 22.** Suzuki reaction of aryl bromides with substituted phenylboronic acids catalysed by **Scheme 10.** Suzuki reaction of aryl halides with phenylboronic acid catalysed by complex **1a** or **1b**: **Scheme 10.** Suzuki reaction of aryl halides with phenylboronic acid catalysed by complex **1a** or **1b**: The first reported use of a thiosemicarbazone in the Suzuki reaction. **Scheme 10.** Suzuki reaction of aryl halides with phenylboronic acid catalysed by complex **1a** or **1b**: The first reported use of a thiosemicarbazone in the Suzuki reaction.

The first reported use of a thiosemicarbazone in the Suzuki reaction.

hydroxynaphthaldehyde thiosemicarbazones with bipyridine or terpyridine supporting ligands (Figure 4) [118]. The tridentate ligands are bonded via N, S, and O donors and the dinuclear complexes are bridged via thiolate and phenolate groups. The complexes were examined for their **Scheme 11.** Microwave-promoted Suzuki–Miyaura cross-coupling of aryl halides with phenylboronic **Scheme 11.** Microwave-promoted Suzuki–Miyaura cross-coupling of aryl halides with phenylboronic acid catalysed by complex **8**. **Scheme 11.** Microwave-promoted Suzuki–Miyaura cross-coupling of aryl halides with phenylboronic acid catalysed by complex **8**.

activity in the Suzuki–Miyaura reaction for some aryl bromides and iodides with phenyl boronic acid. Relatively good activity was observed although it was much less than that shown by similar palladium complexes. Similar *O*,*N*,*S*-bonded nickel complexes **26** derived from 9,10 phenanthrenequinone thiosemicarbazone, 9,10-phenanthrenequinone *N*-methylthiosemicarbazone and 9,10-phenanthrenequinone *N*-phenylthiosemicarbazone have also been reported by Anitha et al*.*, acid catalysed by complex **8**. Bidentate complexes **3** and **4** prepared and characterised by Paul et al*.*, and described above in relation to their catalytic activity in the Heck reaction (Figure 1), were also examined for their possible use in the Suzuki–Miyaura reaction [95,102]. The coupling of phenylboronic acid with *p*-Bidentate complexes **3** and **4** prepared and characterised by Paul et al*.*, and described above in relation to their catalytic activity in the Heck reaction (Figure 1), were also examined for their possible use in the Suzuki–Miyaura reaction [95,102]. The coupling of phenylboronic acid with *p*bromoacetophenone, *p*-bromobenzaldehyde, or *p*-bromobenzonitrile was investigated using both the mono-ligand complex **3** containing PPh<sup>3</sup> as a supporting ligand and the bis-ligand phosphane-free Bidentate complexes **3** and **4** prepared and characterised by Paul et al., and described above in relation to their catalytic activity in the Heck reaction (Figure 1), were also examined for their possible use in the Suzuki–Miyaura reaction [95,102]. The coupling of phenylboronic acid with *p*-bromoacetophenone, *p*-bromobenzaldehyde, or *p*-bromobenzonitrile was investigated using both the mono-ligand complex **3** containing PPh<sup>3</sup> as a supporting ligand and the bis-ligand phosphane-free

recorded for the former complex while lower, but still high, TONs (up to 8,800) and TOFs (up to 733

) were recorded in the latter case. The mono-ligand complexes showed tolerance to water although the best results were obtained in dry conditions. The reaction involving *p*-bromoacetophenone using the mono-ligand complex **3** was even successful at 25 °C giving a conversion of 99%, TON of 100,000,

**Scheme 12.** Suzuki reaction of aryl bromides with phenylboronic acid catalysed by complex **3**.

**Scheme 12.** Suzuki reaction of aryl bromides with phenylboronic acid catalysed by complex **3**.

The phosphane-free complex **9** was reported by Castiñeiras et al*.* (Figure 2) [103]. The tridentate coordination of the dianionic ligand derived from 5-acetylbarbituric-4*N*-dimethylthiosemicarbazone was confirmed by XRD crystallography. In the reaction between phenylboronic acid and bromobenzene, *p*-bromoanisole, *p*-bromonitrobenzene and the corresponding chloro-derivatives, conversions of between 46 and 78% were observed for the aryl bromides, while somewhat lower values from 21 to 32% were found for the chlorides (Scheme 13). The authors postulated that, since the ligand is dianionic, the mechanism involves initial oxidative addition of the aryl halide and cycling between palladium +2 and +4 oxidation states as had previously been proposed for other Pd catalysts possessing pincer ligands, rather than via the 0 and +2 states [104,105]. However, it should

The phosphane-free complex **9** was reported by Castiñeiras et al*.* (Figure 2) [103]. The tridentate coordination of the dianionic ligand derived from 5-acetylbarbituric-4*N*-dimethylthiosemicarbazone was confirmed by XRD crystallography. In the reaction between phenylboronic acid and bromobenzene, *p*-bromoanisole, *p*-bromonitrobenzene and the corresponding chloro-derivatives, conversions of between 46 and 78% were observed for the aryl bromides, while somewhat lower values from 21 to 32% were found for the chlorides (Scheme 13). The authors postulated that, since the ligand is dianionic, the mechanism involves initial oxidative addition of the aryl halide and cycling between palladium +2 and +4 oxidation states as had previously been proposed for other Pd catalysts possessing pincer ligands, rather than via the 0 and +2 states [104,105]. However, it should

) were recorded in the latter case. The mono-ligand complexes showed tolerance to water although the best results were obtained in dry conditions. The reaction involving *p*-bromoacetophenone using the mono-ligand complex **3** was even successful at 25 °C giving a conversion of 99%, TON of 100,000,

) were

) were

bromoacetophenone, *p*-bromobenzaldehyde, or *p*-bromobenzonitrile was investigated using both the

but these complexes gave only rather moderate results for Suzuki–Miyaura couplings [119].

as base, temperature 95–110 °C) and very high TONs (100,000) and TOFs (up to 11,111 h–<sup>1</sup>

acid catalysed by complex **8**.

complex **4** (Scheme 12). Relatively mild conditions were used (ethanol-toluene or PEG solvent, NaOH as base, temperature 95–110 ◦C) and very high TONs (100,000) and TOFs (up to 11,111 h–1) were recorded for the former complex while lower, but still high, TONs (up to 8,800) and TOFs (up to 733 h–1) were recorded in the latter case. The mono-ligand complexes showed tolerance to water although the best results were obtained in dry conditions. The reaction involving *p*-bromoacetophenone using the mono-ligand complex **3** was even successful at 25 ◦C giving a conversion of 99%, TON of 100,000, and TOF of 5,000 h–1 . complex **4** (Scheme 12). Relatively mild conditions were used (ethanol-toluene or PEG solvent, NaOH as base, temperature 95–110 °C) and very high TONs (100,000) and TOFs (up to 11,111 h–<sup>1</sup> ) were recorded for the former complex while lower, but still high, TONs (up to 8,800) and TOFs (up to 733 h–<sup>1</sup> ) were recorded in the latter case. The mono-ligand complexes showed tolerance to water although the best results were obtained in dry conditions. The reaction involving *p*-bromoacetophenone using the mono-ligand complex **3** was even successful at 25 °C giving a conversion of 99%, TON of 100,000, and TOF of 5,000 h–<sup>1</sup> .

mono-ligand complex **3** containing PPh<sup>3</sup> as a supporting ligand and the bis-ligand phosphane-free

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

**Scheme 10.** Suzuki reaction of aryl halides with phenylboronic acid catalysed by complex **1a** or **1b**:

**Scheme 11.** Microwave-promoted Suzuki–Miyaura cross-coupling of aryl halides with phenylboronic

Bidentate complexes **3** and **4** prepared and characterised by Paul et al*.*, and described above in relation to their catalytic activity in the Heck reaction (Figure 1), were also examined for their possible

The first reported use of a thiosemicarbazone in the Suzuki reaction.

**Scheme 12.** Suzuki reaction of aryl bromides with phenylboronic acid catalysed by complex **3**. **Scheme 12.** Suzuki reaction of aryl bromides with phenylboronic acid catalysed by complex **3**.

The phosphane-free complex **9** was reported by Castiñeiras et al*.* (Figure 2) [103]. The tridentate coordination of the dianionic ligand derived from 5-acetylbarbituric-4*N*-dimethylthiosemicarbazone was confirmed by XRD crystallography. In the reaction between phenylboronic acid and bromobenzene, *p*-bromoanisole, *p*-bromonitrobenzene and the corresponding chloro-derivatives, conversions of between 46 and 78% were observed for the aryl bromides, while somewhat lower values from 21 to 32% were found for the chlorides (Scheme 13). The authors postulated that, since the ligand is dianionic, the mechanism involves initial oxidative addition of the aryl halide and cycling between palladium +2 and +4 oxidation states as had previously been proposed for other Pd catalysts possessing pincer ligands, rather than via the 0 and +2 states [104,105]. However, it should The phosphane-free complex **9** was reported by Castiñeiras et al. (Figure 2) [103]. The tridentate coordination of the dianionic ligand derived from 5-acetylbarbituric-4*N*-dimethylthiosemicarbazone was confirmed by XRD crystallography. In the reaction between phenylboronic acid and bromobenzene, *p*-bromoanisole, *p*-bromonitrobenzene and the corresponding chloro-derivatives, conversions of between 46 and 78% were observed for the aryl bromides, while somewhat lower values from 21 to 32% were found for the chlorides (Scheme 13). The authors postulated that, since the ligand is dianionic, the mechanism involves initial oxidative addition of the aryl halide and cycling between palladium +2 and +4 oxidation states as had previously been proposed for other Pd catalysts possessing pincer ligands, rather than via the 0 and +2 states [104,105]. However, it should be noted that it is now generally accepted that cross-couplings catalysed by cyclometallated Pd(II) complexes proceed via a Pd(II) to Pd(0) pathway and that Pd(0) species are the active catalysts [57]. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 11 of 42 be noted that it is now generally accepted that cross-couplings catalysed by cyclometallated Pd(II) complexes proceed via a Pd(II) to Pd(0) pathway and that Pd(0) species are the active catalysts [57].

**Scheme 13.** Suzuki reaction of aryl halides with phenylboronic acid catalysed by complex **9**. **Scheme 13.** Suzuki reaction of aryl halides with phenylboronic acid catalysed by complex **9**.

In 2012 the group of Bhattacharya reported new thiosemicarbazone complexes **(10, 11)** of palladium with 1-nitroso-2-naphtholate or quinolin-8-olate supporting ligands (Figure 2) [106]. The thiosemicarbazone ligands were derivatives of benzaldehyde with a range of para-substituents in order to investigate their effect on catalytic activity. The complexes contain two 5-membered rings and only the configuration where the two nitrogens are trans to each other was observed. Catalysis of the Suzuki–Miyaura reaction by complexes **10** and **11** was studied, with optimisation of certain parameters being carried out with phenylboronic acid and *p*-bromoacetophenone as substrates. Using catalyst loadings of 0.001 mol%, 100% conversions were obtained after 24 h in PEG at 120 °C using either NaOH or Cs2CO<sup>3</sup> as base (Scheme 14). Under these conditions, TONs of up to 100,000 and TOFs of up to 16,667 h–<sup>1</sup> were recorded. Reduction of the loading to 0.0001 mol% gave slightly lower conversions as did replacement of *p*-bromoacetophenone with the less reactive *p*bromobenzaldehyde or *p*-bromobenzonitrile. Other halo-derivatives were also examined and, as expected, *p*-iodoacetophenone also gave 100% conversion while *p*-chloroacetophenone required a higher loading of 0.1 mol% to achieve a similar result. Interestingly, low but significant yields, 10– In 2012 the group of Bhattacharya reported new thiosemicarbazone complexes (**10**, **11**) of palladium with 1-nitroso-2-naphtholate or quinolin-8-olate supporting ligands (Figure 2) [106]. The thiosemicarbazone ligands were derivatives of benzaldehyde with a range of para-substituents in order to investigate their effect on catalytic activity. The complexes contain two 5-membered rings and only the configuration where the two nitrogens are trans to each other was observed. Catalysis of the Suzuki–Miyaura reaction by complexes **10** and **11** was studied, with optimisation of certain parameters being carried out with phenylboronic acid and *p*-bromoacetophenone as substrates. Using catalyst loadings of 0.001 mol%, 100% conversions were obtained after 24 h in PEG at 120 ◦C using either NaOH or Cs2CO<sup>3</sup> as base (Scheme 14). Under these conditions, TONs of up to 100,000 and TOFs of up to 16,667 h–1 were recorded. Reduction of the loading to 0.0001 mol% gave slightly lower conversions as did replacement of *p*-bromoacetophenone with the less reactive *p*-bromobenzaldehyde or *p*-bromobenzonitrile. Other halo-derivatives were also examined and, as expected, *p*-iodoacetophenone also gave 100% conversion while *p*-chloroacetophenone required a higher loading of 0.1 mol% to achieve a similar result. Interestingly, low but significant yields, 10–12%,

12%, of the product of coupling *p*-fluoroacetophenone with phenylboronic acid were observed with

protonated thiosemicarbazone and *N*,*O*-donor ligands remain coordinated, followed by oxidative addition of the aryl halide. If indeed the active species is as proposed, it could be of interest to determine if it remains active for reuse in repeated cycles. In an attempt to produce analogous complexes with 2-picolinic acid as the supporting ligand, Dutta and Bhattacharya, instead of the expected mono-ligand complexes, obtained the bis-ligand complexes **12** with a rare cis-configuration and also a second product which was postulated to be a polymeric bridged complex containing a tridentate cyclometallated ligand (Figure 2) [107]. This was confirmed by cleavage of the bridges by triphenylphosphine to give the mononuclear complexes of the type **13a** whose structures were also confirmed by X-ray crystallography. The two sets of complexes were examined for their potential as catalysts for the Suzuki–Miyaura reaction for a range of aryl halides and substituted phenylboronic acids (Scheme 15). Very good conversions were observed for most of the reactions with aryl iodides and bromides under relatively mild conditions (PEG as solvent, 120 °C, NaOH as base, 1–8 h) and catalyst loadings of 0.001 mol%, while aryl chlorides required higher catalyst loadings of 0.1 mol% to achieve comparable results. The *p*-methoxyphenyl and *p*-chlorophenylboronic acids reacted more sluggishly than phenylboronic acid itself. Of the two sets of complexes, the mono-ligand complexes gave somewhat superior results and this was attributed to the presence of the triphenyphosphine supporting ligand. For both sets of complexes, no additional ligand was needed and the authors argue that this implies that the ligands in the pre-catalyst do not dissociate and that they stabilize the intermediate Pd(0) species. The same research group has also reported further examples of the monoligand cyclometallated complex with PPh<sup>3</sup> supporting ligand (complexes **13b**, **14**, **15**). These were prepared by a slightly different route and, together with a non-cyclometallated complex containing a bidentate thiosemicarbazone ligand as well as PPh3, were examined for their activity in the coupling of *p*-haloacetophenones with phenylboronic acid (Scheme 16) [108]. Results similar to those given

of the product of coupling *p*-fluoroacetophenone with phenylboronic acid were observed with 1 mol% catalyst loading. Although no specific studies of the likely mechanism were described, the authors favoured a process involving initial formation of a zerovalent Pd species, in which the protonated thiosemicarbazone and *N*,*O*-donor ligands remain coordinated, followed by oxidative addition of the aryl halide. If indeed the active species is as proposed, it could be of interest to determine if it remains active for reuse in repeated cycles. In an attempt to produce analogous complexes with 2-picolinic acid as the supporting ligand, Dutta and Bhattacharya, instead of the expected mono-ligand complexes, obtained the bis-ligand complexes **12** with a rare cis-configuration and also a second product which was postulated to be a polymeric bridged complex containing a tridentate cyclometallated ligand (Figure 2) [107]. This was confirmed by cleavage of the bridges by triphenylphosphine to give the mononuclear complexes of the type **13a** whose structures were also confirmed by X-ray crystallography. The two sets of complexes were examined for their potential as catalysts for the Suzuki–Miyaura reaction for a range of aryl halides and substituted phenylboronic acids (Scheme 15). Very good conversions were observed for most of the reactions with aryl iodides and bromides under relatively mild conditions (PEG as solvent, 120 ◦C, NaOH as base, 1–8 h) and catalyst loadings of 0.001 mol%, while aryl chlorides required higher catalyst loadings of 0.1 mol% to achieve comparable results. The *p*-methoxyphenyl and *p*-chlorophenylboronic acids reacted more sluggishly than phenylboronic acid itself. Of the two sets of complexes, the mono-ligand complexes gave somewhat superior results and this was attributed to the presence of the triphenyphosphine supporting ligand. For both sets of complexes, no additional ligand was needed and the authors argue that this implies that the ligands in the pre-catalyst do not dissociate and that they stabilize the intermediate Pd(0) species. The same research group has also reported further examples of the mono-ligand cyclometallated complex with PPh<sup>3</sup> supporting ligand (complexes **13b**, **14**, **15**). These were prepared by a slightly different route and, together with a non-cyclometallated complex containing a bidentate thiosemicarbazone ligand as well as PPh3, were examined for their activity in the coupling of *p*-haloacetophenones with phenylboronic acid (Scheme 16) [108]. Results similar to those given above were obtained, the cyclometalated complexes giving the better results. Notably, coupling of the fluoro-derivative could also be achieved with these catalysts. Analogous cyclometallated palladium complexes **16** based on 3,4-dichloroacetophenone thiosemicarbazone have also been reported by Yan et al. [109]. These complexes were screened for their activity in the Suzuki–Miyaura reaction and the most promising of the four, a dinuclear complex with a 1,1'-bisdiphenylphosphinoferrocene bridging supporting ligand, was used for further study. Reactions were carried out for 24–48 h in air or argon, using DMF as a solvent, K3PO<sup>4</sup> as base and a temperature of 130 ◦C, using a range of aryl bromides and chlorides and various aryl boronic acids (Scheme 17). Substitution on the boronic acid had no major effect except for 2-methoxyphenyl boronic acid, which gave lower yields, possibly because of steric effects. The aryl bromides all gave moderately good to excellent yields while the chlorides, as expected, gave lower conversions except for *p*-nitrochlorobenzene. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 12 of 42 above were obtained, the cyclometalated complexes giving the better results. Notably, coupling of the fluoro-derivative could also be achieved with these catalysts. Analogous cyclometallated palladium complexes **16** based on 3,4-dichloroacetophenone thiosemicarbazone have also been reported by Yan et al*.* [109]. These complexes were screened for their activity in the Suzuki–Miyaura reaction and the most promising of the four, a dinuclear complex with a 1,1' bisdiphenylphosphinoferrocene bridging supporting ligand, was used for further study. Reactions were carried out for 24–48 h in air or argon, using DMF as a solvent, K3PO<sup>4</sup> as base and a temperature of 130 °C, using a range of aryl bromides and chlorides and various aryl boronic acids (Scheme 17). Substitution on the boronic acid had no major effect except for 2-methoxyphenyl boronic acid, which gave lower yields, possibly because of steric effects. The aryl bromides all gave moderately good to excellent yields while the chlorides, as expected, gave lower conversions except for *p*nitrochlorobenzene.

**Scheme 14.** Suzuki reaction of aryl bromides with phenylboronic acid catalysed by complex **10** or **11**. **Scheme 14.** Suzuki reaction of aryl bromides with phenylboronic acid catalysed by complex **10** or **11**.

**Scheme 15.** Suzuki reaction of aryl bromides with substituted phenylboronic acids catalysed by

**Scheme 16.** Suzuki reaction of *p*-bromo-acetophenone with phenylboronic acid catalysed by complex

complex **12a** or **13a**.

**13b**, **14** or **15**.

nitrochlorobenzene.

nitrochlorobenzene.

above were obtained, the cyclometalated complexes giving the better results. Notably, coupling of the fluoro-derivative could also be achieved with these catalysts. Analogous cyclometallated palladium complexes **16** based on 3,4-dichloroacetophenone thiosemicarbazone have also been reported by Yan et al*.* [109]. These complexes were screened for their activity in the Suzuki–Miyaura reaction and the most promising of the four, a dinuclear complex with a 1,1' bisdiphenylphosphinoferrocene bridging supporting ligand, was used for further study. Reactions were carried out for 24–48 h in air or argon, using DMF as a solvent, K3PO<sup>4</sup> as base and a temperature of 130 °C, using a range of aryl bromides and chlorides and various aryl boronic acids (Scheme 17). Substitution on the boronic acid had no major effect except for 2-methoxyphenyl boronic acid, which gave lower yields, possibly because of steric effects. The aryl bromides all gave moderately good to excellent yields while the chlorides, as expected, gave lower conversions except for *p*-

above were obtained, the cyclometalated complexes giving the better results. Notably, coupling of the fluoro-derivative could also be achieved with these catalysts. Analogous cyclometallated palladium complexes **16** based on 3,4-dichloroacetophenone thiosemicarbazone have also been reported by Yan et al*.* [109]. These complexes were screened for their activity in the Suzuki–Miyaura reaction and the most promising of the four, a dinuclear complex with a 1,1' bisdiphenylphosphinoferrocene bridging supporting ligand, was used for further study. Reactions were carried out for 24–48 h in air or argon, using DMF as a solvent, K3PO<sup>4</sup> as base and a temperature of 130 °C, using a range of aryl bromides and chlorides and various aryl boronic acids (Scheme 17). Substitution on the boronic acid had no major effect except for 2-methoxyphenyl boronic acid, which gave lower yields, possibly because of steric effects. The aryl bromides all gave moderately good to excellent yields while the chlorides, as expected, gave lower conversions except for *p*-

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 12 of 42

**Scheme 15.** Suzuki reaction of aryl bromides with substituted phenylboronic acids catalysed by complex **12a** or **13a**. **Scheme 15.** Suzuki reaction of aryl bromides with substituted phenylboronic acids catalysed by complex **12a** or **13a**. **Scheme 15.** Suzuki reaction of aryl bromides with substituted phenylboronic acids catalysed by complex **12a** or **13a**.

**Scheme 16.** Suzuki reaction of *p*-bromo-acetophenone with phenylboronic acid catalysed by complex **Scheme 16.** Suzuki reaction of *p*-bromo-acetophenone with phenylboronic acid catalysed by complex **13b**, **14** or **15**. **Scheme 16.** Suzuki reaction of *p*-bromo-acetophenone with phenylboronic acid catalysed by complex *Catalysts*  **13b**, **14** or **15**. **2020**, *10*, x FOR PEER REVIEW 13 of 42

**Scheme 17.** Suzuki reaction of aryl halides with substituted phenylboronic acids catalysed by complex **16**. **Scheme 17.** Suzuki reaction of aryl halides with substituted phenylboronic acids catalysed by complex **16**.

The complex **17** was reported by Pandiarajan et al*.* (Figure 3) [110]. The dianionic ligand binds through S, N, and O donors and the complex is air and moisture stable. It catalysed the Suzuki– Miyaura reaction in refluxing DMF with K2CO<sup>3</sup> base with very good conversions after 3 h for a number of aryl bromides and boronic acids (Scheme 18). Coupling of *p*-iodoacetophenone was also achieved with excellent conversion while with the analogous chloro-derivative moderate yields of product were obtained after 12 h. In the same year, another phosphane supported thiosemicarbazone palladium complex, **18**, was reported by Verma et al*.* (Figure 3) [111]. The thiosemicarbazone in this case is derived from a sugar aldehyde and the complex from the analogous semicarbazone was also prepared. These ligands were shown by structural studies to bind to the metal in a bidentate manner. The authors were particularly interested in the catalytic activity of these complexes in the coupling of aryl chlorides with boronic acids and found that this could be achieved in good to excellent yields at ambient temperatures using a catalyst loading of 0.2 mol% in EtOH, with K2CO<sup>3</sup> as base and reaction times of just 30–90 min (Scheme 19). At lower catalyst loadings, however, the reaction times were much longer and yields were also reduced. The authors were able to demonstrate that the catalysts retained their activity after five cycles. The complex **17** was reported by Pandiarajan et al. (Figure 3) [110]. The dianionic ligand binds through S, N, and O donors and the complex is air and moisture stable. It catalysed the Suzuki–Miyaura reaction in refluxing DMF with K2CO<sup>3</sup> base with very good conversions after 3 h for a number of aryl bromides and boronic acids (Scheme 18). Coupling of *p*-iodoacetophenone was also achieved with excellent conversion while with the analogous chloro-derivative moderate yields of product were obtained after 12 h. In the same year, another phosphane supported thiosemicarbazone palladium complex, **18**, was reported by Verma et al. (Figure 3) [111]. The thiosemicarbazone in this case is derived from a sugar aldehyde and the complex from the analogous semicarbazone was also prepared. These ligands were shown by structural studies to bind to the metal in a bidentate manner. The authors were particularly interested in the catalytic activity of these complexes in the coupling of aryl chlorides with boronic acids and found that this could be achieved in good to excellent yields at ambient temperatures using a catalyst loading of 0.2 mol% in EtOH, with K2CO<sup>3</sup> as base and reaction times of just 30–90 min (Scheme 19). At lower catalyst loadings, however, the reaction times were much longer and yields were also reduced. The authors were able to demonstrate that the catalysts retained their activity after five cycles.

h at 100 °C in DMF and with K2CO<sup>3</sup> as base, good to excellent conversions were obtained using a 0.05 mol% catalyst loading. Aryl chlorides, however, gave rather poor conversions. Tests were carried out in order to determine the nature of the catalyst and it was concluded that the active species was heterogeneous and possibly composed of Pd(0) nanoparticles. The complexes used in this study and in the study mentioned in the previous paragraph [111] are of additional interest in that they employ chiral ligands. Although in these studies, possible applications in asymmetric catalysis were not explored, the amenability of thiosemicarbazone ligands to functionalisation with chiral groups could

provide a promising avenue for future work.

In an attempt to develop a phosphane-free catalyst, the group of Kostas synthesised a binuclear

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 15 of 42

**Scheme 18.** Suzuki reaction of aryl bromides with substituted phenylboronic acids catalysed by complex **17**. **Scheme 18.** Suzuki reaction of aryl bromides with substituted phenylboronic acids catalysed by complex **17**. **Scheme 18.** Suzuki reaction of aryl bromides with substituted phenylboronic acids catalysed by complex **17**.

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 15 of 42

**Scheme 19.** Suzuki reaction of aryl chlorides with phenylboronic acid catalysed by complex **18**. **Scheme 19.** Suzuki reaction of aryl chlorides with phenylboronic acid catalysed by complex **18**.

**Scheme 19.** Suzuki reaction of aryl chlorides with phenylboronic acid catalysed by complex **18**. **Scheme 20.** Suzuki reaction of aryl bromides with phenylboronic acid catalysed by complex **19**. The use of aqueous media for carrying out catalytic reactions has many attractions and in 2017, **Scheme 20.** Suzuki reaction of aryl bromides with phenylboronic acid catalysed by complex **19**. The use of aqueous media for carrying out catalytic reactions has many attractions and in 2017, Matsinha et al*.* reported the synthesis of two water-soluble palladium complexes **20a** and **20b** In an attempt to develop a phosphane-free catalyst, the group of Kostas synthesised a binuclear palladium complex **19** with a ligand derived from β-D-glucopyranosyl-thiosemicarbazone (Figure 3) [112]. The complex was characterised spectroscopically and investigated as a potential catalyst for the Suzuki–Miyaura reaction between aryl bromides and phenyl boronic acid (Scheme 20). After 24 h at 100 ◦C in DMF and with K2CO<sup>3</sup> as base, good to excellent conversions were obtained using a 0.05 mol% catalyst loading. Aryl chlorides, however, gave rather poor conversions. Tests were carried out in order to determine the nature of the catalyst and it was concluded that the active species was heterogeneous and possibly composed of Pd(0) nanoparticles. The complexes used in this study and in the study mentioned in the previous paragraph [111] are of additional interest in that they employ chiral ligands. Although in these studies, possible applications in asymmetric catalysis were not explored, the amenability of thiosemicarbazone ligands to functionalisation with chiral groups could provide a promising avenue for future work. **Scheme 18.** Suzuki reaction of aryl bromides with substituted phenylboronic acids catalysed by complex **17**. **Scheme 19.** Suzuki reaction of aryl chlorides with phenylboronic acid catalysed by complex **18**.

Matsinha et al*.* reported the synthesis of two water-soluble palladium complexes **20a** and **20b**

containing sulfonated-thiosemicarbazone ligands (Figure 3) [113]. In both complexes, the ligand is

Satisfactory results were obtained, although it should be noted that rather long reaction times (24 h) and higher catalyst loadings (1 mol%) were employed than were usual for reactions in non-aqueous and higher catalyst loadings (1 mol%) were employed than were usual for reactions in non-aqueous media. An investigation into the reusability of the catalysts indicated that activity drops off quite

media. An investigation into the reusability of the catalysts indicated that activity drops off quite rapidly and that during the fourth cycle activity was low. The authors speculate that this could be **Scheme 20.** Suzuki reaction of aryl bromides with phenylboronic acid catalysed by complex **19**. **Scheme 20.** Suzuki reaction of aryl bromides with phenylboronic acid catalysed by complex **19**.

rapidly and that during the fourth cycle activity was low. The authors speculate that this could be due either to leaching of the active catalyst during the extraction step or to partial decomposition of the active species. However, the possibility that the catalyst was the precursor to a heterogeneous system which then degraded quickly was ruled out by the authors, since the mercury drop test for such cases failed to affect the catalytic activity to any significant extent. An aqueous media was also employed by Baruah et al*.* for the complex **21** (Figure 3) [114]. In this case, the supporting ligand is imidazole and the thiosemicarbazone adopts bidentate coordination as a monoanion. After a number of optimisation runs, the authors examined the coupling of a range of aryl halides and aryl boronic acids using this complex as a precatalyst. Ambient temperatures were employed with K2CO<sup>3</sup> as the base and a catalyst loading of 1.18 mol%. For most of the aryl bromides, good conversions were achieved after 2–6 h, while the aryl chorides examined needed an elevated temperature (60 °C) and due either to leaching of the active catalyst during the extraction step or to partial decomposition of the active species. However, the possibility that the catalyst was the precursor to a heterogeneous system which then degraded quickly was ruled out by the authors, since the mercury drop test for such cases failed to affect the catalytic activity to any significant extent. An aqueous media was also employed by Baruah et al*.* for the complex **21** (Figure 3) [114]. In this case, the supporting ligand is imidazole and the thiosemicarbazone adopts bidentate coordination as a monoanion. After a number of optimisation runs, the authors examined the coupling of a range of aryl halides and aryl boronic acids using this complex as a precatalyst. Ambient temperatures were employed with K2CO<sup>3</sup> as the base and a catalyst loading of 1.18 mol%. For most of the aryl bromides, good conversions were achieved after 2–6 h, while the aryl chorides examined needed an elevated temperature (60 °C) and longer reaction times for comparable results. The complex itself was not soluble in water and was The use of aqueous media for carrying out catalytic reactions has many attractions and in 2017, Matsinha et al*.* reported the synthesis of two water-soluble palladium complexes **20a** and **20b** containing sulfonated-thiosemicarbazone ligands (Figure 3) [113]. In both complexes, the ligand is tridentate, and the vacant position is occupied by a tertiary phosphine (PPh<sup>3</sup> in **20a** and 1,3,5-triaza-7-phosphaadamantane in **20b**). The complexes displayed good stability in water. Catalytic coupling of a range of aryl bromides with aryl boronic acids was investigated in water at 70 °C using Na2CO<sup>3</sup> as base and TBAB (tetrabutylammonium bromide) as a phase-transfer mediator (Scheme 21). Satisfactory results were obtained, although it should be noted that rather long reaction times (24 h) and higher catalyst loadings (1 mol%) were employed than were usual for reactions in non-aqueous media. An investigation into the reusability of the catalysts indicated that activity drops off quite The use of aqueous media for carrying out catalytic reactions has many attractions and in 2017, Matsinha et al. reported the synthesis of two water-soluble palladium complexes **20a** and **20b** containing sulfonated-thiosemicarbazone ligands (Figure 3) [113]. In both complexes, the ligand is tridentate, and the vacant position is occupied by a tertiary phosphine (PPh<sup>3</sup> in **20a** and 1,3,5-triaza-7-phosphaadamantane in **20b**). The complexes displayed good stability in water. Catalytic coupling of a range of aryl bromides with aryl boronic acids was investigated in water at 70 ◦C using Na2CO<sup>3</sup> as base and TBAB (tetrabutylammonium bromide) as a phase-transfer mediator (Scheme 21). Satisfactory results were obtained, although it should be noted that rather long reaction times (24 h) and higher catalyst loadings (1 mol%) were employed than were usual for reactions in non-aqueous media. An investigation into the reusability of the catalysts indicated that activity drops off quite

system which then degraded quickly was ruled out by the authors, since the mercury drop test for such cases failed to affect the catalytic activity to any significant extent. An aqueous media was also employed by Baruah et al*.* for the complex **21** (Figure 3) [114]. In this case, the supporting ligand is imidazole and the thiosemicarbazone adopts bidentate coordination as a monoanion. After a number of optimisation runs, the authors examined the coupling of a range of aryl halides and aryl boronic acids using this complex as a precatalyst. Ambient temperatures were employed with K2CO<sup>3</sup> as the base and a catalyst loading of 1.18 mol%. For most of the aryl bromides, good conversions were achieved after 2–6 h, while the aryl chorides examined needed an elevated temperature (60 °C) and longer reaction times for comparable results. The complex itself was not soluble in water and was rapidly and that during the fourth cycle activity was low. The authors speculate that this could be due either to leaching of the active catalyst during the extraction step or to partial decomposition of the active species. However, the possibility that the catalyst was the precursor to a heterogeneous system which then degraded quickly was ruled out by the authors, since the mercury drop test for such cases failed to affect the catalytic activity to any significant extent. An aqueous media was also employed by Baruah et al. for the complex **21** (Figure 3) [114]. In this case, the supporting ligand is imidazole and the thiosemicarbazone adopts bidentate coordination as a monoanion. After a number of optimisation runs, the authors examined the coupling of a range of aryl halides and aryl boronic acids using this complex as a precatalyst. Ambient temperatures were employed with K2CO<sup>3</sup> as the base and a catalyst loading of 1.18 mol%. For most of the aryl bromides, good conversions were achieved after 2–6 h, while the aryl chorides examined needed an elevated temperature (60 ◦C) and longer reaction times for comparable results. The complex itself was not soluble in water and was used as a suspension and it was suspected that the actual catalyst could be a Pd(0) species. Support for this came from a mercury drop test, which inhibited catalytic activity. The activity of the catalyst falls of in subsequent cycles but no significant leaching of palladium was observed. The catalyst isolated after a first cycle was therefore examined by TEM, SEM-EDX, and XRD and was determined to consist of Pd(0) nanoparticles whish are presumed to be formed by dissociation of the ligands from the initial complex during the reaction. SEM-EDX examination of these nanoparticles indicated that they are possibly stabilized by surface thiosemicarbazone ligands. They were found to have an initial size of 1.5–2.0 nm, but after successive runs they aggregated to larger particles with lower activity. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 16 of 42 used as a suspension and it was suspected that the actual catalyst could be a Pd(0) species. Support for this came from a mercury drop test, which inhibited catalytic activity. The activity of the catalyst falls of in subsequent cycles but no significant leaching of palladium was observed. The catalyst isolated after a first cycle was therefore examined by TEM, SEM-EDX, and XRD and was determined to consist of Pd(0) nanoparticles whish are presumed to be formed by dissociation of the ligands from the initial complex during the reaction. SEM-EDX examination of these nanoparticles indicated that they are possibly stabilized by surface thiosemicarbazone ligands. They were found to have an initial size of 1.5–2.0 nm, but after successive runs they aggregated to larger particles with lower activity.

**Scheme 21.** Aqueous Suzuki reaction of aryl bromides with substituted phenylboronic acids catalysed by complex **20a** or **20b**. **Scheme 21.** Aqueous Suzuki reaction of aryl bromides with substituted phenylboronic acids catalysed by complex **20a** or **20b**.

Dharani et al*.* reported a series of palladium complexes **22** derived from 3-acetyl-7-methoxy-2*H*chromen-2-one thiosemicarbazones (Figure 3) [115]. Three of the products **(22a**–**c)** proved to be tetranuclear complexes in which ligands are bonded via S, N, and C, cyclometallation having taken place by activation of the ortho-C–H bond. The palladium atoms are connected via thiolate bridges. The fourth complex, with phenyl substitution on the terminal nitrogen of the thiosemicarbazide, was the mononuclear species **22d**. All of the complexes were screened for activity as catalysts for the Suzuki–Miyaura reaction and one them **(22b)** was chosen for further study. Using a 0.125 mol% loading of the complex, EtOH-H2O as solvent, K2CO<sup>3</sup> as base, and a temperature of 70 °C, good conversions were obtained for the coupling of phenyl boronic acid with a range of aryl halides including chloroquinolines. The results were found to compare well with those obtained for other tetranuclear palladium complexes in aqueous conditions. The catalyst isolated from the reaction could be used up to four more times with only partial loss of activity. In further cycles, however, a 50% loss of activity occurred. A mechanism was proposed involving initial cleavage of the tetranuclear complex into a mononuclear species followed by a Pd(II)-Pd(IV) oxidative addition/elimination sequence. The fall-off in activity in fifth and successive cycles was ascribed to the gradual aggregation of the mononuclear species to form less active nanoparticles, evidence for which was obtained by powder X-ray diffraction studies. More recently, Bakir et al*.* have reported similar tetranuclear complexes derived from di-thienyl ketone thiosemicarbazone [116]. These were screened for their possible use as precatalysts in the Suzuki–Miyaura reaction but the results were only moderate. This was ascribed by the authors to be at least partly due to the polymeric nature and Dharani et al. reported a series of palladium complexes **22** derived from 3-acetyl-7-methoxy-2*H*-chromen-2-one thiosemicarbazones (Figure 3) [115]. Three of the products (**22a**–**c**) proved to be tetranuclear complexes in which ligands are bonded via S, N, and C, cyclometallation having taken place by activation of the ortho-C–H bond. The palladium atoms are connected via thiolate bridges. The fourth complex, with phenyl substitution on the terminal nitrogen of the thiosemicarbazide, was the mononuclear species **22d**. All of the complexes were screened for activity as catalysts for the Suzuki–Miyaura reaction and one them (**22b**) was chosen for further study. Using a 0.125 mol% loading of the complex, EtOH-H2O as solvent, K2CO<sup>3</sup> as base, and a temperature of 70 ◦C, good conversions were obtained for the coupling of phenyl boronic acid with a range of aryl halides including chloroquinolines. The results were found to compare well with those obtained for other tetranuclear palladium complexes in aqueous conditions. The catalyst isolated from the reaction could be used up to four more times with only partial loss of activity. In further cycles, however, a 50% loss of activity occurred. A mechanism was proposed involving initial cleavage of the tetranuclear complex into a mononuclear species followed by a Pd(II)-Pd(IV) oxidative addition/elimination sequence. The fall-off in activity in fifth and successive cycles was ascribed to the gradual aggregation of the mononuclear species to form less active nanoparticles, evidence for which was obtained by powder X-ray diffraction studies. More recently, Bakir et al. have reported similar tetranuclear complexes derived from di-thienyl ketone thiosemicarbazone [116]. These were screened for their possible use as precatalysts in the Suzuki–Miyaura reaction but the results were only moderate. This was ascribed by the authors to be at least partly due to the polymeric nature and insolubility of the complex.

membered rings (Figure 4) [117]. The authors hypothesised that, in view of the previously observed improvements in catalytic efficiency due to the presence of phosphine supporting ligands, the use of a diphosphine could potentially enhance this even further. Indeed, compared with other analogous complexes prepared by these workers [95], superior results were seen. Good conversions with high

bromides at 95 °C in EtOH-toluene with Cs2CO<sup>3</sup> as base and catalyst loadings of 0.001–0.0001 mol% (Scheme 22). Chlorides also engaged quite readily in the coupling reaction with somewhat higher catalyst loadings and slightly modified conditions, while aryl fluorides could also be coupled with the unsubstituted phenyl boronic acid at 130 °C in PEG using NaOBu*<sup>t</sup>* as base and with a 1 mol%

) were observed for a number of aryl iodides and

insolubility of the complex.

catalyst loading.

TONs (up to 980,000) and TOFs (up to 326,667 h–<sup>1</sup>

Cationic complexes **23** of the type [Pd(dppe)L]NO<sup>3</sup> (dppe = 1,2-bis(diphenylphosphino)ethane), where L is a bidentate thiosemicarbazone ligand derived from a *p*-substituted benzaldehyde were prepared by Thapa et al., and structurally characterised, confirming the formation of *N*,*S*-chelated 5-membered rings (Figure 4) [117]. The authors hypothesised that, in view of the previously observed improvements in catalytic efficiency due to the presence of phosphine supporting ligands, the use of a diphosphine could potentially enhance this even further. Indeed, compared with other analogous complexes prepared by these workers [95], superior results were seen. Good conversions with high TONs (up to 980,000) and TOFs (up to 326,667 h–1) were observed for a number of aryl iodides and bromides at 95 ◦C in EtOH-toluene with Cs2CO<sup>3</sup> as base and catalyst loadings of 0.001–0.0001 mol% (Scheme 22). Chlorides also engaged quite readily in the coupling reaction with somewhat higher catalyst loadings and slightly modified conditions, while aryl fluorides could also be coupled with the unsubstituted phenyl boronic acid at 130 ◦C in PEG using NaOBu*<sup>t</sup>* as base and with a 1 mol% catalyst loading. **Figure 4.** Representative metal complexes of thiosemicarbazones as catalysts for the Suzuki–Miyaura and other coupling reactions (Part C).

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 17 of 42

**Scheme 22.** Suzuki reaction of aryl bromides with substituted phenylboronic acids catalysed by complex **23**. **Scheme 22.** Suzuki reaction of aryl bromides with substituted phenylboronic acids catalysed by complex **23**.

Catalysis of the Suzuki–Miyaura reaction by nickel complexes has attracted attention in recent years due to the greater accessibility of nickel and also its greater activity in certain cases. Thiosemicarbazone complexes of nickel, however, have been much less investigated than their palladium counterparts. In 2011, Datta et al*.* reported the synthesis of mono- and dinuclear nickel complexes **24** and **25**, respectively, derived from salicylaldehyde, 2-hydroxyacetophenone and 2 hydroxynaphthaldehyde thiosemicarbazones with bipyridine or terpyridine supporting ligands (Figure 4) [118]. The tridentate ligands are bonded via N, S, and O donors and the dinuclear complexes are bridged via thiolate and phenolate groups. The complexes were examined for their activity in the Suzuki–Miyaura reaction for some aryl bromides and iodides with phenyl boronic acid. Relatively good activity was observed although it was much less than that shown by similar palladium complexes. Similar *O*,*N*,*S*-bonded nickel complexes **26** derived from 9,10 phenanthrenequinone thiosemicarbazone, 9,10-phenanthrenequinone *N*-methylthiosemicarbazone and 9,10-phenanthrenequinone *N*-phenylthiosemicarbazone have also been reported by Anitha et al*.*, Catalysis of the Suzuki–Miyaura reaction by nickel complexes has attracted attention in recent years due to the greater accessibility of nickel and also its greater activity in certain cases. Thiosemicarbazone complexes of nickel, however, have been much less investigated than their palladium counterparts. In 2011, Datta et al. reported the synthesis of mono- and dinuclear nickel complexes **24** and **25**, respectively, derived from salicylaldehyde, 2-hydroxyacetophenone and 2-hydroxynaphthaldehyde thiosemicarbazones with bipyridine or terpyridine supporting ligands (Figure 4) [118]. The tridentate ligands are bonded via N, S, and O donors and the dinuclear complexes are bridged via thiolate and phenolate groups. The complexes were examined for their activity in the Suzuki–Miyaura reaction for some aryl bromides and iodides with phenyl boronic acid. Relatively good activity was observed although it was much less than that shown by similar palladium complexes. Similar *O*,*N*,*S*-bonded nickel complexes **26** derived from 9,10-phenanthrenequinone thiosemicarbazone, 9,10-phenanthrenequinone *N*-methylthiosemicarbazone and 9,10-phenanthr enequinone *N*-phenylthiosemicarbazone have also been reported by Anitha et al., but these complexes gave only rather moderate results for Suzuki–Miyaura couplings [119].

but these complexes gave only rather moderate results for Suzuki–Miyaura couplings [119]. Although it is not a normal Suzuki–Miyaura reaction, we may also mention here the application of the palladium thiosemicarbazonato complex **27** as a catalyst for the synthesis of diaryl ketones via the C–C coupling reaction between aryl aldehydes and aryl boronic acids reported by Prabhu and Ramesh (Scheme 23) [120]. Optimal conditions were found to be 110 ◦C in toluene in the presence of Cs2O<sup>3</sup> and using 5 mol% of the complex. The scope of the reaction was demonstrated by the synthesis of diaryl ketones from the reaction of a wide variety of aromatic and heteroaromatic aldehydes with phenyl boronic acid as well as from the reaction of a selection of aryl boronic acids with benzaldehyde. Satisfactory to excellent isolated yields were obtained.

catalysed by thiosemicarbazone complexes.

benzaldehyde. Satisfactory to excellent isolated yields were obtained.

Although it is not a normal Suzuki–Miyaura reaction, we may also mention here the application of the palladium thiosemicarbazonato complex **27** as a catalyst for the synthesis of diaryl ketones via the C–C coupling reaction between aryl aldehydes and aryl boronic acids reported by Prabhu and Ramesh (Scheme 23) [120]. Optimal conditions were found to be 110 °C in toluene in the presence of Cs2O<sup>3</sup> and using 5 mol% of the complex. The scope of the reaction was demonstrated by the synthesis of diaryl ketones from the reaction of a wide variety of aromatic and heteroaromatic aldehydes with phenyl boronic acid as well as from the reaction of a selection of aryl boronic acids with

**Scheme 23.** Synthesis of diaryl ketones by carbon–carbon coupling reaction between aryl aldehydes and aryl boronic acids. **Scheme 23.** Synthesis of diaryl ketones by carbon–carbon coupling reaction between aryl aldehydes and aryl boronic acids.

*2.3. Sonogashira and Related Reactions* Table 2 summarises representative conditions and yields for Suzuki–Miyaura reactions catalysed by thiosemicarbazone complexes.


terminal alkynes with haloorganics has developed into an essential tool for the synthetic organic chemist (Scheme 24) [1,5,9]. Palladium or copper complexes are generally employed to facilitate this **Table 2.** Suzuki–Miyaura reactions catalysed by thiosemicarbazone complexes: representative conditions and yields <sup>1</sup> .

Since the first report by Sonogashira in 1975 [121], the metal complex-catalysed coupling of

1 conditions refer to reactions involving aryl bromides and phenyl or aryl boronic acids. <sup>2</sup> ligand donor atoms. <sup>3</sup> microwave irradiation <sup>4</sup> aryl chlorides were used. <sup>5</sup> Aryl aldehydes used instead of aryl halides.
