**3. Carbon–Heteroatom Coupling Reactions**

Although the majority of the work on metal complex catalysed coupling reactions concerns the formation of carbon–carbon bonds, carbon–heteroatom coupling reactions have also been widely studied. These predominantly concern the formation of carbon–nitrogen bonds for systems where non-catalysed coupling is not possible or very difficult. Reactions in this category include the Pd-catalysed arylation of amines (the Buchwald–Hartwig coupling shown in Scheme 33) [131,132], the Pd-catalysed formation of C–N, C–O or C–S bonds using aryl boronic acids and suitable heteroatom derivatives (the Chan-Lam coupling shown in Scheme 34) [133,134], and also the metal-catalysed Ullmann reaction (Scheme 35) [135,136]. Representative metal complexes catalyzed carbon–heteroatom coupling reactions are shown in Figure 7; see also in Figures 2 and 4. Priyarega et al*.* reported nickel thiosemicarbazone complexes **34** with Ph3P supporting ligand that catalyse the formation of biphenyl in good yield [129]. From the experimental data, it is stated that a large amount (0.05 mol) of complex is used for 0.01 mol of PhBr but presumably this is a typographical error with the correct amount of complex to be probably 0.05 mmol. Güveli et al*.* have prepared a series of thiosemicarbazone complexes **35** derived from *o*-hydroxyacetophenone in which either *O*,*N*,*S*- or *O*,*N*,*N*-tridentate coordination is observed [130]. In addition to structural and computational studies, the authors also examined the coupling of PhMgBr with PhBr in the presence of these compounds. The *ONN*-complexes gave higher yields compared to the *ONS*-complexes and this was ascribed to the larger size of the S atom and also to the higher charge on the metal. A range of aryl halides were employed by Anitha et al*.* in their study of Ni(II) complexes containing *O*,*N*,*S*-

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 24 of 42

A number of thiosemicarbazone complexes of palladium have been screened as potential catalysts for C–N coupling reactions. Many of these have also been investigated as catalysts for C–C couplings and have therefore been described above in the relevant sections. Thus, the mixed-ligand benzaldehyde thiosemicarbazone Pd-complexes **10**, **11**, **12**, and **13a** (Figure 2) prepared by Dutta et al., described previously [106,107], are also active catalysts for the Buchwald–Hartwig arylation of primary and secondary amines (Scheme 36). The addition of the hindered XPhos ligand (2-dicyclohexylphosphino-20 ,40 ,60 -triisopropylbiphenyl) was required for good activity and it was presumed that it was necessary to stabilize the active species, the other ligands having been displaced. Although somewhat higher catalyst loadings were found to be necessary for the C–N couplings than were used in the Suzuki–Miyaura reaction, catalytic efficiency was comparable to other palladium complexes under similar conditions. Very good results were also obtained under slightly milder conditions when the same group employed the cyclopalladated complexes **13b**, **14**, and **15** (Figure 2) for the coupling of selected aryl halides with aniline, providing TONs of 10,000 and TOFs of up to 833 h–1 (Scheme 37) [108]. A much broader range of aryl halides were used by Prabhu and Ramesh in their study of the catalytic activity of the complex **36** (Figure 7), [PdBr(PPh3)L], where L is a bidentate chelating monoanionic ligand derived from 1-naphthaldehyde thiosemicarbazone [137]. Good to excellent results were obtained under relatively mild conditions (2-BuOH as solvent, K2CO<sup>3</sup> as base, 100 ◦C, N<sup>2</sup> atmosphere, 24 h) using a 500:1 of substrate to complex molar ratio for the coupling of aromatic and heteroaromatic bromides with cyclic secondary amines (Scheme 38). Dibromides could also be successfully coupled with the same secondary amines under similar conditions. The coupling of aryl chlorides took place using slightly longer reaction times (30 h) and with somewhat lower conversions. It was found that the catalyst could be used twice without any detectable loss of activity but that gradual loss of activity was observed for subsequent cycles. Apart from the aforementioned monophosphine complexes, a recent study reports the synthesis of a cationic Pd thiosemicarbazone complex **23** (R = OCH3; see in Figure 4) containing a diphosphine which, apart from catalysing the Suzuki–Miyaura reaction (see above) was also found to be effective in the Buchwald–Hartwig arylation [117]. Aryl bromides and iodides gave good conversions in the reaction with primary or secondary amines in either dioxane at 100 ◦C or PEG at 150 ◦C with low catalyst loadings (0.01 mol%) in the presence of NaOBu*<sup>t</sup>* . Aryl chlorides, however, generally gave poor yields. tricoordinating thiosemicarbazone ligands, which have also been described above as catalysts for the Suzuki–Miyaura and Sonogashira reactions (see complexes **26** in Figure 4) [119]. Moderate to excellent yields of biaryls were obtained under mild conditions (Et2O, 4 h) and with catalyst loadings of 0.2 mol% (Scheme 32). TONs of up to 93 and TOFs of up to 2 h–<sup>1</sup> were recorded. Reactions for aryl halides with electron withdrawing substituents were found to give slightly higher yields than those with electron-donating substituents, while ortho-substituted aryls gave lower yields. Overall, their catalytic efficiency was found to compare favorably with previously reported catalysts. **Scheme 32.** Kumada–Tamao–Corriu reaction of aryl halides with phenylmagnesium chloride catalysed by Ni complexes **26**. **3. Carbon–Heteroatom Coupling Reactions**  Although the majority of the work on metal complex catalysed coupling reactions concerns the formation of carbon–carbon bonds, carbon–heteroatom coupling reactions have also been widely studied. These predominantly concern the formation of carbon–nitrogen bonds for systems where non-catalysed coupling is not possible or very difficult. Reactions in this category include the Pdcatalysed arylation of amines (the Buchwald–Hartwig coupling shown in Scheme 33) [131,132], the Pd-catalysed formation of C–N, C–O or C–S bonds using aryl boronic acids and suitable heteroatom derivatives (the Chan-Lam coupling shown in Scheme 34) [133,134], and also the metal-catalysed Ullmann reaction (Scheme 35) [135,136]. Representative metal complexes catalyzed carbon– heteroatom coupling reactions are shown in Figure 7; see also in Figures 2 and 4.

**Scheme 33.** Buchwald–Hartwig reaction. **Scheme 33.** Buchwald–Hartwig reaction.

catalysed by Ni complexes **26**.

**3. Carbon–Heteroatom Coupling Reactions** 

**Scheme 33.** Buchwald–Hartwig reaction.

heteroatom coupling reactions are shown in Figure 7; see also in Figures 2 and 4.

Priyarega et al*.* reported nickel thiosemicarbazone complexes **34** with Ph3P supporting ligand that catalyse the formation of biphenyl in good yield [129]. From the experimental data, it is stated that a large amount (0.05 mol) of complex is used for 0.01 mol of PhBr but presumably this is a typographical error with the correct amount of complex to be probably 0.05 mmol. Güveli et al*.* have prepared a series of thiosemicarbazone complexes **35** derived from *o*-hydroxyacetophenone in which either *O*,*N*,*S*- or *O*,*N*,*N*-tridentate coordination is observed [130]. In addition to structural and computational studies, the authors also examined the coupling of PhMgBr with PhBr in the presence of these compounds. The *ONN*-complexes gave higher yields compared to the *ONS*-complexes and this was ascribed to the larger size of the S atom and also to the higher charge on the metal. A range of aryl halides were employed by Anitha et al*.* in their study of Ni(II) complexes containing *O*,*N*,*S*tricoordinating thiosemicarbazone ligands, which have also been described above as catalysts for the Suzuki–Miyaura and Sonogashira reactions (see complexes **26** in Figure 4) [119]. Moderate to excellent yields of biaryls were obtained under mild conditions (Et2O, 4 h) and with catalyst loadings of 0.2 mol% (Scheme 32). TONs of up to 93 and TOFs of up to 2 h–<sup>1</sup> were recorded. Reactions for aryl halides with electron withdrawing substituents were found to give slightly higher yields than those with electron-donating substituents, while ortho-substituted aryls gave lower yields. Overall, their

catalytic efficiency was found to compare favorably with previously reported catalysts.

**Scheme 32.** Kumada–Tamao–Corriu reaction of aryl halides with phenylmagnesium chloride

Although the majority of the work on metal complex catalysed coupling reactions concerns the formation of carbon–carbon bonds, carbon–heteroatom coupling reactions have also been widely studied. These predominantly concern the formation of carbon–nitrogen bonds for systems where non-catalysed coupling is not possible or very difficult. Reactions in this category include the Pdcatalysed arylation of amines (the Buchwald–Hartwig coupling shown in Scheme 33) [131,132], the Pd-catalysed formation of C–N, C–O or C–S bonds using aryl boronic acids and suitable heteroatom derivatives (the Chan-Lam coupling shown in Scheme 34) [133,134], and also the metal-catalysed Ullmann reaction (Scheme 35) [135,136]. Representative metal complexes catalyzed carbon–

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 25 of 42

**Scheme 34. Scheme 34.** Chan Chan-Lam coupling. -Lam coupling. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 25 of 42

**Scheme 35.** Classic Ullmann reaction (top) and Ullmann-type reaction (bottom). **Scheme 35.** Classic Ullmann reaction (top) and Ullmann-type reaction (bottom). **Scheme 35.** Classic Ullmann reaction (top) and Ullmann-type reaction (bottom).

**Figure 7.** Representative metal complexes of thiosemicarbazones as catalysts for carbon–heteroatom **Figure 7.** Representative metal complexes of thiosemicarbazones as catalysts for carbon–heteroatom coupling reactions. **Figure 7.** Representative metal complexes of thiosemicarbazones as catalysts for carbon–heteroatom coupling reactions. at 150 °C with low catalyst loadings (0.01 mol%) in the presence of NaOBu*<sup>t</sup>* . Aryl chlorides, however, generally gave poor yields.

good conversions in the reaction with primary or secondary amines in either dioxane at 100 °C or PEG

catalyst loadings were found to be necessary for the C–N couplings than were used in the Suzuki– Miyaura reaction, catalytic efficiency was comparable to other palladium complexes under similar catalyst loadings were found to be necessary for the C–N couplings than were used in the Suzuki– Miyaura reaction, catalytic efficiency was comparable to other palladium complexes under similar conditions. Very good results were also obtained under slightly milder conditions when the same group **Scheme 36.** Buchwald–Hartwig arylation of primary and secondary amines catalysed by complexes **12**a or **13a**. **Scheme 36.** Buchwald–Hartwig arylation of primary and secondary amines catalysed by complexes **12a** or **13a**.

broader range of aryl halides were used by Prabhu and Ramesh in their study of the catalytic activity of the complex **36** (Figure 7), [PdBr(PPh3)L], where L is a bidentate chelating monoanionic ligand derived from 1-naphthaldehyde thiosemicarbazone [137]. Good to excellent results were obtained

**Scheme 37.** Buchwald–Hartwig reaction of phenyl bromide with aniline catalysed by complexes **13b**,

**Scheme 38.** Buchwald–Hartwig reaction of aryl- and heteroaryl bromides with cyclic secondary

*N*-arylation of heterocycles can been achieved by using a palladium catalyst derived from 9,10 phenanthrenequinone thiosemicarbazones **37** (Figure 7) as well as the corresponding semicarbazone as reported by Anitha et al. [138]. The ligand in these complexes is tridentate monoanionic and the most efficient one in initial screening experiments was that derived from phenanthrenequinone *N*-

broader range of aryl halides were used by Prabhu and Ramesh in their study of the catalytic activity of the complex **36** (Figure 7), [PdBr(PPh3)L], where L is a bidentate chelating monoanionic ligand derived from 1-naphthaldehyde thiosemicarbazone [137]. Good to excellent results were obtained

(Scheme 37) [108]. A much

(Scheme 37) [108]. A much

halides with aniline, providing TONs of 10,000 and TOFs of up to 833 h–<sup>1</sup>

**14**, or **15**.

amines catalysed by complex **36**.

generally gave poor yields.

generally gave poor yields.

**Scheme 36.** Buchwald–Hartwig arylation of primary and secondary amines catalysed by complexes

under relatively mild conditions (2-BuOH as solvent, K2CO<sup>3</sup> as base, 100 °C, N<sup>2</sup> atmosphere, 24 h) using a 500:1 of substrate to complex molar ratio for the coupling of aromatic and heteroaromatic bromides with cyclic secondary amines (Scheme 38). Dibromides could also be successfully coupled with the same secondary amines under similar conditions. The coupling of aryl chlorides took place using slightly longer reaction times (30 h) and with somewhat lower conversions. It was found that the catalyst could be used twice without any detectable loss of activity but that gradual loss of activity was observed for subsequent cycles. Apart from the aforementioned monophosphine complexes, a recent study reports the synthesis of a cationic Pd thiosemicarbazone complex **23** (R = OCH3; see in Figure 4) containing a diphosphine which, apart from catalysing the Suzuki–Miyaura reaction (see above) was also found to be effective in the Buchwald–Hartwig arylation [117]. Aryl bromides and iodides gave good conversions in the reaction with primary or secondary amines in either dioxane at 100 °C or PEG

under relatively mild conditions (2-BuOH as solvent, K2CO<sup>3</sup> as base, 100 °C, N<sup>2</sup> atmosphere, 24 h) using a 500:1 of substrate to complex molar ratio for the coupling of aromatic and heteroaromatic bromides with cyclic secondary amines (Scheme 38). Dibromides could also be successfully coupled with the same secondary amines under similar conditions. The coupling of aryl chlorides took place using slightly longer reaction times (30 h) and with somewhat lower conversions. It was found that the catalyst could be used twice without any detectable loss of activity but that gradual loss of activity was observed for subsequent cycles. Apart from the aforementioned monophosphine complexes, a recent study reports the synthesis of a cationic Pd thiosemicarbazone complex **23** (R = OCH3; see in Figure 4) containing a diphosphine which, apart from catalysing the Suzuki–Miyaura reaction (see above) was also found to be effective in the Buchwald–Hartwig arylation [117]. Aryl bromides and iodides gave good conversions in the reaction with primary or secondary amines in either dioxane at 100 °C or PEG

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 26 of 42

. Aryl chlorides, however,

. Aryl chlorides, however,

**Scheme 37.** Buchwald–Hartwig reaction of phenyl bromide with aniline catalysed by complexes **13b**, **14**, or **15**. **Scheme 37.** Buchwald–Hartwig reaction of phenyl bromide with aniline catalysed by complexes **13b**, **14**, or **15**. **14**, or **15**.

$$\begin{array}{ccccc} & & \mathsf{R} & \mathsf{Complex} & \mathsf{36} \\ \mathsf{ArBr} & + & \mathsf{N} & \mathsf{N} & \mathsf{0} \\ \mathsf{FArBr} & \mathsf{R} & \mathsf{K}\_2\mathsf{CO}\_3, \mathsf{2-BuOH} & \mathsf{Ar} & \mathsf{N} \\ & & & \mathsf{100} & \mathsf{°C}, \mathsf{24} & \mathsf{h} \\ \end{array}$$

amines catalysed by complex **36**.

at 150 °C with low catalyst loadings (0.01 mol%) in the presence of NaOBu*<sup>t</sup>*

at 150 °C with low catalyst loadings (0.01 mol%) in the presence of NaOBu*<sup>t</sup>*

**Scheme 38.** Buchwald–Hartwig reaction of aryl- and heteroaryl bromides with cyclic secondary **Scheme 38.** Buchwald–Hartwig reaction of aryl- and heteroaryl bromides with cyclic secondary **Scheme 38.** Buchwald–Hartwig reaction of aryl- and heteroaryl bromides with cyclic secondary amines catalysed by complex **36**.

amines catalysed by complex **36**. *N*-arylation of heterocycles can been achieved by using a palladium catalyst derived from 9,10 phenanthrenequinone thiosemicarbazones **37** (Figure 7) as well as the corresponding semicarbazone as reported by Anitha et al. [138]. The ligand in these complexes is tridentate monoanionic and the most efficient one in initial screening experiments was that derived from phenanthrenequinone *N*-*N*-arylation of heterocycles can been achieved by using a palladium catalyst derived from 9,10 phenanthrenequinone thiosemicarbazones **37** (Figure 7) as well as the corresponding semicarbazone as reported by Anitha et al. [138]. The ligand in these complexes is tridentate monoanionic and the most efficient one in initial screening experiments was that derived from phenanthrenequinone *N*-*N*-arylation of heterocycles can been achieved by using a palladium catalyst derived from 9,10-phenanthrenequinone thiosemicarbazones **37** (Figure 7) as well as the corresponding semicarbazone as reported by Anitha et al. [138]. The ligand in these complexes is tridentate monoanionic and the most efficient one in initial screening experiments was that derived from phenanthrenequinone *N*-methylthiosemicarbazone. A range of aromatic and heteroaromatic chlorides, bromides and iodides were employed for coupling with imidazole in DMSO at 110 ◦C in the presence of KOH and 0.75 mol% of the complex. Moderate to very good yields were obtained, and it was shown that the reaction had the potential to be extended to other related heterocycles. Due to the fact that the best solvent for the reaction was DMSO, the authors favour a Pd(II)/Pd(IV) mechanistic oxidative addition pathway over a Pd(0)/Pd(II) one.

Copper complexes are also known to catalyse C–N coupling reactions. These are often Cu(I) complexes but the first instance of a thiosemicarbazone copper complex catalysed C–N coupling involves the Cu(II) oxidation state as reported by Shan et al. [139]. The use of copper compounds in this oxidation state offers some advantages since they are generally more convenient to handle. The catalytic procedure involved in situ complex formation from CuCl<sup>2</sup> (10 mol%) and excess ligand, 3-methoxy, 4-hydroxybenzaldehyde thiosemicarbazone in the presence of K2CO<sup>3</sup> together with the appropriate substrates in DMF at 110 ◦C. Under these conditions, moderate to good yields of coupled products were obtained from the reaction of imidazole or benzimidazole with aryl bromides or iodides. The use of Cu(I) instead of CuCl<sup>2</sup> gave inferior results under the same conditions and the authors speculate that the reaction proceeds via a Cu(II)/Cu(IV) oxidative-addition pathway which is favoured by the stabilisation of the copper intermediate by the electron-rich ligand and the consequent decrease in the oxidation potential. Another instance of Cu(II) catalysed *N*-arylation was also recently reported by Gogoi et al. [140]. This involves a Chan-Lam coupling of a number of aryl or heteroaryl boronic acids with aniline or with *N*-containing heterocycles. Here again the complex was formed in situ, in this case from Cu(OAc)<sup>2</sup> and 2,5-dimethoxy benzaldehyde-4-phenylthiosemicarbazide; use of the preformed complex gave inferior results. Moderate to very good yields were obtained under mild conditions (room temperature, aqueous DMF as solvent, Et3N as base, 10 mol% catalyst loading) which compare very favorably with previously reported results for similar systems.

*N*-alkylation of amines by means of alkyl alcohols can be catalysed by Cu(I) complexes and this has been demonstrated for complexes **38** (Figure 7) containing 2-(2-(diphenylphosphino) benzylidene) thiosemicarbazone ligands by Ramachandran et al. (Scheme 39) [141]. In these complexes, the ligand is bound to the metal through P, N and S. A range of substituted benzyl alcohols were employed together with a number substituted aminobenzothiazoles as well as 1-amino-diphenylthiazole, benzimidazole and 2,6-diaminopyridine. *n*-Butanol and *n*-hexanol were also successfully used as the alkylating agent. The conditions used involved a catalyst loading of 0.1 mol%, KOH as base, toluene as solvent and heating to 100 ◦C for 12 h. Good to excellent yields, TONs of up to 990 and TOFs of up to 83 h–1 were obtained, in particular for complex in which R is the CH<sup>3</sup> group. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 28 of 42

**Scheme 39.** *N*-alkylation of amines with various alcohols catalysed by Cu complex **38** (R = CH3). **Scheme 39.** *N*-alkylation of amines with various alcohols catalysed by Cu complex **38** (R = CH<sup>3</sup> ).

Several reports have also appeared from the group of Viswanathamurthi and co-workers concerning C–N coupling reactions catalysed by ruthenium complexes [74,142–145]. The initial report briefly describes the benzylation of aniline catalysed by ruthenium hydroxyquinoline– thiosemicarbazone complexes **39** (Figure 7) at 100 °C under nitrogen in the presence of KOBu*<sup>t</sup>* . Good conversions were obtained using a 1000:1 substrate to catalyst molar ratio [74]. Subsequent reports from this group describe XRD structurally characterised complexes containing tridentate *P*,*N*,*S*chelating thiosemicarbazone derivatives of 2-diphenylphosphinobenzaldehyde as ligands in which the effect of terminal *N*-substitution is examined. Thus, the complexes [RuCl(CO)(EPh3)L] **(40)** (Figure 7), where E = P, As and L = 2-(2-(diphenylphosphino) benzylidene)-*N*-R-thiosemicarbazone (R = H, CH<sup>3</sup> or Ph) were prepared and their catalytic activity studied for the *N*-alkylation of heteroaromatic amines by alcohols [142]. Optimisation experiments indicated that the complex containing the 2-(2-(diphenylphosphino)benzylidene)-*N*-methylthiosemicarbazone was found to give the best results, with a 0.5 mol% catalyst loading in the presence of KOH in toluene at 100 °C for 12 h (Scheme 40). Good to very good yields were obtained for the alkylation using *p*-C6H4CH2OH or ferrocenylCH2OH and primary amines such as aniline, 2-aminopyridine 2-aminobenzothiazole while dialkylation of 2,6-diaminopyridine could also be affected. In addition to straightforward alkylations, Several reports have also appeared from the group of Viswanathamurthi and co-workers concerning C–N coupling reactions catalysed by ruthenium complexes [74,142–145]. The initial report briefly describes the benzylation of aniline catalysed by ruthenium hydroxyquinoline–thiosemicarbazone complexes **39** (Figure 7) at 100 ◦C under nitrogen in the presence of KOBu*<sup>t</sup>* . Good conversions were obtained using a 1000:1 substrate to catalyst molar ratio [74]. Subsequent reports from this group describe XRD structurally characterised complexes containing tridentate *P*,*N*,*S*-chelating thiosemicarbazone derivatives of 2-diphenylphosphino benzaldehyde as ligands in which the effect of terminal *N*-substitution is examined. Thus, the complexes [RuCl(CO)(EPh3)L] **(40)** (Figure 7), where E = P, As and L = 2-(2-(diphenylphosphino) benzylidene)-*N*-R-thiosemicarbazone (R = H, CH<sup>3</sup> or Ph) were prepared and their catalytic activity studied for the *N*-alkylation of heteroaromatic amines by alcohols [142]. Optimisation experiments indicated that the complex containing the 2-(2-(diphenylphosphino)benzylidene)- *N*-methylthiosemicarbazone was found to give the best results, with a 0.5 mol% catalyst loading in the presence of KOH in toluene at 100 ◦C for 12 h (Scheme 40). Good to very good yields were obtained for the alkylation using *p*-C6H4CH2OH or ferrocenylCH2OH and primary amines such as aniline, 2-aminopyridine 2-aminobenzothiazole while dialkylation of 2,6-diaminopyridine

products, viz. benzazoles, benzoxazoles, or benzothiazoles. In a subsequent report, comparable catalytic activity was demonstrated for complexes of the type [RuCl(CO)(AsPh3)(L)] **(41)** where L = 2-(2-(diphenylphosphino)benzylidene)-*N*-ethyl-thiosemicarbazone or 2-(2-(diphenylphosphino) benzylidene)-*N*-cyclohexyl-thiosemicarbazone (Figure 7) [143]. The authors propose that the mechanism for the reaction is via a so-called "borrowed hydrogen" pathway, whereby the alcohol is catalytically dehydrogenated to the corresponding aldehyde, which then condenses with the amine

when 2-nitropyridine was employed as substrate initial reduction to the primary amine and

(R = CH3, E = P).

Pd (het)ArBr + *N*-

could also be affected. In addition to straightforward alkylations, when 2-nitropyridine was employed as substrate initial reduction to the primary amine and subsequent alkylation could be achieved, while for aminobenzene ortho-substituted with NH2, OH or SH, the alkylation reaction with primary alcohols gave good yields of 2-substituted heterocyclic products, viz. benzazoles, benzoxazoles, or benzothiazoles. In a subsequent report, comparable catalytic activity was demonstrated for complexes of the type [RuCl(CO)(AsPh3)(L)] (**41**) where L = 2-(2-(diphenylphosphino)benzylidene)-*N*-ethyl-thiosemi carbazone or 2-(2-(diphenylphosphino) benzylidene)-*N*-cyclohexyl-thiosemicarbazone (Figure 7) [143]. The authors propose that the mechanism for the reaction is via a so-called "borrowed hydrogen" pathway, whereby the alcohol is catalytically dehydrogenated to the corresponding aldehyde, which then condenses with the amine to give an intermediate imine, which is subsequently hydrogenated by the catalyst. A further series of ruthenium complexes, bearing the 2-(2-(diphenylphosphino) benzylidene)-*N*-ethyl-thiosemicarbazone ligand, L, were prepared, namely [RuCl(CO)(PPh3)L], [RuH(CO)(PPh3)2L], [RuCl(PPh3)2L], [RuCl(dmso)2L], and [RuL2] [144]. Of these complexes, the last one showed little or no catalytic activity while the first three complexes showed the best results and were studied in more detail. Using conditions comparable with those in the previous studies, and with similar substrates, the complexes were found to give good to excellent conversions. *N*-Alkylation of sulfonamides was also very successful. We may also mention here that the complex [RuL2], where L is the monoanionic ligand derived from 2-(2-(diphenylphosphino)-benzylidene)-*N*-phenylthiosemicarbazone, has also been screened for its catalytic activity in the *N*-alkylation of primary amines [145]. In this investigation, the complex proved to be inferior to other semicarbazone complexes that were examined and was not subjected to further detailed study. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 29 of 42 to give an intermediate imine, which is subsequently hydrogenated by the catalyst. A further series of ruthenium complexes, bearing the 2-(2-(diphenylphosphino)benzylidene)-*N*-ethylthiosemicarbazone ligand, L, were prepared, namely [RuCl(CO)(PPh3)L], [RuH(CO)(PPh3)2L], [RuCl(PPh3)2L], [RuCl(dmso)2L], and [RuL2] [144]. Of these complexes, the last one showed little or no catalytic activity while the first three complexes showed the best results and were studied in more detail. Using conditions comparable with those in the previous studies, and with similar substrates, the complexes were found to give good to excellent conversions. *N*-Alkylation of sulfonamides was also very successful. We may also mention here that the complex [RuL2], where L is the monoanionic ligand derived from 2-(2-(diphenylphosphino)-benzylidene)-*N*-phenylthiosemicarbazone, has also been screened for its catalytic activity in the *N*-alkylation of primary amines [145]. In this investigation, the complex proved to be inferior to other semicarbazone complexes that were examined and was not subjected to further detailed study. Apart from the above C–N coupling reactions, there has also been one report by Suganthy et al. of C–O coupling catalysed by a thiosemicarbazone complex [146]. Thus the coupling of *p*-cresol with a number of aryl halides containing electron-withdrawing or electron-donating groups could be effected, with moderate to very good yields, in DMF at 80 °C after 12 h in an inert atmosphere using a 1 mol% loading of the catalyst [PdCl(PPh3)L] (**42**), where L is the bidentate *N*,*S*-chelating ligand derived from the deprotonation of 3-methyl-thiophene-2-carboxaldehyde thiosemicarbazone (Figure 7). Published results of the use of thiosemicarbazone complexes as described above for Cheteroatom coupling reactions are summarised in Table 4.

**Scheme 40.** *N*-alkylation of (hetero)aromatic amine/amides with alcohols catalysed by Ru complex **40 Scheme 40.** *N*-alkylation of (hetero)aromatic amine/amides with alcohols catalysed by Ru complex **40** (R = CH<sup>3</sup> , E = P).

**Table 4.** Carbon–heteroatom coupling reactions catalysed by thiosemicarbazone complexes: representative conditions and yields. **Metal Substrates <sup>T</sup> (°C) Solvent Time (h) Ligand <sup>1</sup> Base Catalyst (mol%) Yield (%) Ref.** Apart from the above C–N coupling reactions, there has also been one report by Suganthy et al. of C–O coupling catalysed by a thiosemicarbazone complex [146]. Thus the coupling of *p*-cresol with a number of aryl halides containing electron-withdrawing or electron-donating groups could be effected, with moderate to very good yields, in DMF at 80 ◦C after 12 h in an inert atmosphere using a 1 mol% loading of the catalyst [PdCl(PPh3)L] (**42**), where L is the bidentate *N*,*S*-chelating ligand derived from the deprotonation of 3-methyl-thiophene-2-carboxaldehyde thiosemicarbazone (Figure 7).

Pd ArBr + 2ary amine 145 PEG 24 N,S NaOBu*<sup>t</sup>* 1.0 50–62 [106] Pd ArBr + 1ary/2ary amine 145 PEG 24 N,S NaOBu*<sup>t</sup>* 0.1 100 [107] Published results of the use of thiosemicarbazone complexes as described above for C-heteroatom coupling reactions are summarised in Table 4.

Pd ArBr + 1ary/2ary amine 145 PEG 18 C,N,S NaOBu*<sup>t</sup>* 0.1 100 [107] Pd ArBr + aniline 105 toluene 12–18 C,N,S NaOBu*<sup>t</sup>* 0.01 100 [108] Pd (het)ArBr + 2ary amine 100 2-BuOH 24 N,S K2CO<sup>3</sup> 0.2 77–99 [137]

heterocycle <sup>110</sup> DMSO <sup>10</sup> O,N,S KOH 0.75 <sup>75</sup>–<sup>90</sup> [138]


**Table 4.** Carbon–heteroatom coupling reactions catalysed by thiosemicarbazone complexes: representative conditions and yields.

ligand donor atoms.

### **4. Immobilised and Heterogeneous Catalysts**

Recovery of catalysts after use is an important factor for consideration for all reactions which involve transition metal complexes. Not only it is important because of the often high cost of the catalysts themselves, but it is also important to minimise contamination of the products. This becomes particularly significant when scale-up of a reaction is being planned. For these reasons, a great deal of effort has been made to develop heterogeneous analogues of homogeneous catalytic reactions in which, the catalyst can be reclaimed by straightforward separation procedures although, attractive as it may seem, this is not always without its disadvantages [147], and special consideration must be given to the stability of the catalysts and to leaching phenomena [87]. In the case of thiosemicarbazone complexes, there have been a number of attempts to develop such systems for coupling reactions. By reduction of K2PdCl<sup>4</sup> with hydrazine hydrate in the presence of pyridine-2-carbaldehyde thiosemicarbazone as stabilizer of the nanoparticles, Kostas, Kovala-Demertzi, and co-workers were able to prepare nanoparticles which were characterized by XRD and SEM [148]. They were active catalysts for the Suzuki–Miyaura reaction of phenyl boronic acid with aryl bromides (Scheme 41). Best results were obtained for *p*-bromonitrobenzene and *p*-bromobenzonitrile, which gave excellent conversions in DMF/H2O at 100 ◦C with 0.1% *w*/*w* catalyst loading and with K2CO<sup>3</sup> as base. Higher catalyst loadings (1% *w*/*w*) were required for good yields from the coupling reactions with bromobenzene and *p*-bromoanisole, as well as for reactions at room temperature, which only gave good yields with *p*-BrC6H4NO<sup>2</sup> and *p*-BrC6H4CN. These thiosemicarbazone-derivatized nanoparticles were found to be more efficient catalysts than the homogeneous catalyst Pd(PPh3)<sup>4</sup> under identical reaction conditions. The catalyst could be recovered but was progressively less active in successive cycles.

Bakherad et al. have reported a polystyrene supported complex of palladium with a 1-phenyl-1,2-propanedione-2-oxime thiosemicarbazone ligand [149]. By attaching the ligand to the polystyrene and then reaction with PdCl2(PhCN)<sup>2</sup> followed by reduction with hydrazine hydrate, a Pd(0) species was obtained which was evaluated for its catalytic activity in the acylation of terminal alkynes. Under optimized solvent-free conditions, namely using 1 mol% catalyst with Et3N as base, excellent conversions (97–99%) were obtained after 30 min in air at room temperature for a range of aromatic acyl chlorides as well as cyclohexyl carboxylic acid chloride with phenylacetylene, pent-1-yne, hex-1-yne, Cu (het)ArB(OH)<sup>2</sup> <sup>+</sup>

Cu (het)ArB(OH)<sup>2</sup> <sup>+</sup>*N*-

Ru RCH2OH +

**4. Immobilised and Heterogeneous Catalysts**

and Me3SiC≡CH (Scheme 42). The catalyst could be recovered by centrifugation and was reused several times with only a slight decrease in activity. more efficient catalysts than the homogeneous catalyst Pd(PPh3)<sup>4</sup> under identical reaction conditions. The catalyst could be recovered but was progressively less active in successive cycles. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 31 of 42 *Catalysts* **2020**, *10*, x FOR PEER REVIEW 31 of 42 Bakherad et al*.* have reported a polystyrene supported complex of palladium with a 1-phenyl-1,2-propanedione-2-oxime thiosemicarbazone ligand [149]. By attaching the ligand to the polystyrene

Bakherad et al*.* have reported a polystyrene supported complex of palladium with a 1-phenyl-

BrC6H4NO<sup>2</sup> and *p*-BrC6H4CN. These thiosemicarbazone-derivatized nanoparticles were found to be

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 30 of 42

Cu RCH2OH + 1ary amine 100 toluene 12 P,N,S KOH 0.1–0.2 89–99 [141] Ru RCH2OH + aniline 100 none 6 O,N,S KOBu*<sup>t</sup>* 1.0 61–86 [74] Ru RCH2OH + 1ary amine 100 toluene 12–24 P,N,S KOH 0.5–1.0 45–99 [142] Ru RCH2OH + 1ary amine 100 toluene 12 P,N,S KOH 0.5 79–98 [143] Ru RCH2OH + 1ary amine 100 toluene 12 P,N,S KOH 0.5 59–98 [144]

Pd ArBr/ArI + *p*-cresol 80 DMF 12 N,S K2CO<sup>3</sup> 1.0 62–94 [146]

ligand donor atoms.

Recovery of catalysts after use is an important factor for consideration for all reactions which involve transition metal complexes. Not only it is important because of the often high cost of the catalysts themselves, but it is also important to minimise contamination of the products. This becomes particularly significant when scale-up of a reaction is being planned. For these reasons, a great deal of effort has been made to develop heterogeneous analogues of homogeneous catalytic reactions in which, the catalyst can be reclaimed by straightforward separation procedures although, attractive as it may seem, this is not always without its disadvantages [147], and special consideration must be given to the stability of the catalysts and to leaching phenomena [87]. In the case of thiosemicarbazone complexes, there have been a number of attempts to develop such systems for coupling reactions. By reduction of K2PdCl<sup>4</sup> with hydrazine hydrate in the presence of pyridine-2-carbaldehyde thiosemicarbazone as stabilizer of the nanoparticles, Kostas, Kovala-Demertzi, and co-workers were able to prepare nanoparticles which were characterized by XRD and SEM [148]. They were active catalysts for the Suzuki–Miyaura reaction of phenyl boronic acid with aryl bromides (Scheme 41). Best results were obtained for *p*-bromonitrobenzene and *p*-bromobenzonitrile, which gave excellent conversions in DMF/H2O at 100 °C with 0.1% *w*/*w* catalyst loading and with K2CO<sup>3</sup> as base. Higher catalyst loadings

1

aniline r.t. DMF/H2<sup>O</sup> <sup>14</sup>–<sup>18</sup> N,S Et3<sup>N</sup> 10.0 <sup>74</sup>–<sup>95</sup> [140]

heterocycle r.t. DMF/H2<sup>O</sup> <sup>18</sup>–<sup>24</sup> N,S Et3<sup>N</sup> 10.0 <sup>70</sup>–<sup>94</sup> [140]

sulfonamide <sup>120</sup> toluene <sup>12</sup> P,N,S KOH 0.5 <sup>21</sup>–<sup>99</sup> [144]

**Scheme 41.** Suzuki reaction of aryl bromides with phenylboronic acid catalysed by **Scheme 41.** Suzuki reaction of aryl bromides with phenylboronic acid catalysed by thiosemicarbazonederivatised Pd nanoparticles. 1-yne, and Me3SiC≡CH (Scheme 42). The catalyst could be recovered by centrifugation and was reused several times with only a slight decrease in activity. reused several times with only a slight decrease in activity.

$$\text{ArCOCl} + \text{R} \xrightarrow[\text{Et}^2]{} \underbrace{\text{[PS-ppdot-Pd(0)]}}\_{\text{Et}^2\text{N}, \text{t.t., 0.5 }\text{h}} \cdot \text{ArCO} \xrightarrow[\text{}]{} \text{ArCO} \xrightarrow[\text{}]{} \text{R}$$

**Scheme 42.** Copper- and solvent-free Sonogashira reaction of acid chlorides with terminal alkynes catalysed by 1-phenyl-1,2-propanedione-2-oxime thiosemicarbazone-functionalized polystyrene **Scheme 42.** Copper- and solvent-free Sonogashira reaction of acid chlorides with terminal alkynes catalysed by 1-phenyl-1,2-propanedione-2-oxime thiosemicarbazone-functionalized polystyrene resin-supported Pd(0) complex [PS-ppdot-Pd(0)]. **Scheme 42.** Copper- and solvent-free Sonogashira reaction of acid chlorides with terminal alkynes catalysed by 1-phenyl-1,2-propanedione-2-oxime thiosemicarbazone-functionalized polystyrene resin-supported Pd(0) complex [PS-ppdot-Pd(0)].

resin-supported Pd(0) complex [PS-ppdot-Pd(0)].

Suzuki–Miyaura coupling of various aryl halides with alkenyl boronic acid has been achieved using a Pd(II) thiosemicarbazone complex tethered to a silica support [150]. Aryl halides were coupled with trans-2-phenylvinyl boronic acid in DMF/H2O in the presence of K2CO<sup>3</sup> and catalyst (25 mg per mmol of ArX), under microwave irradiation at 110 °C for 25 min. The reaction was selective for the formation of *E*-stilbenes and the catalyst was readily recovered by filtration. The catalyst could be used for at least six consecutive trials without loss of activity. Absence of palladium in the liquid Suzuki–Miyaura coupling of various aryl halides with alkenyl boronic acid has been achieved using a Pd(II) thiosemicarbazone complex tethered to a silica support [150]. Aryl halides were coupled with trans-2-phenylvinyl boronic acid in DMF/H2O in the presence of K2CO<sup>3</sup> and catalyst (25 mg per mmol of ArX), under microwave irradiation at 110 ◦C for 25 min. The reaction was selective for the formation of *E*-stilbenes and the catalyst was readily recovered by filtration. The catalyst could be used for at least six consecutive trials without loss of activity. Absence of palladium in the liquid phase after filtration suggested that no leaching of the catalyst had occurred during the reaction. Suzuki–Miyaura coupling of various aryl halides with alkenyl boronic acid has been achieved using a Pd(II) thiosemicarbazone complex tethered to a silica support [150]. Aryl halides were coupled with trans-2-phenylvinyl boronic acid in DMF/H2O in the presence of K2CO<sup>3</sup> and catalyst (25 mg per mmol of ArX), under microwave irradiation at 110 °C for 25 min. The reaction was selective for the formation of *E*-stilbenes and the catalyst was readily recovered by filtration. The catalyst could be used for at least six consecutive trials without loss of activity. Absence of palladium in the liquid phase after filtration suggested that no leaching of the catalyst had occurred during the reaction.

phase after filtration suggested that no leaching of the catalyst had occurred during the reaction. Veisi et al*.* have used multi-walled carbon nanotubes to which thiosemicarbazide has been grafted to form supported Cu(I) complexes that are able to catalyse the Ullmann coupling of indole, amines or imidazoles with aryl halides [151]. The coupling reactions were optimally carried out in DMF/Et3N at 80 °C using a substrate:Cu ratio of 50/1 and reaction times ranging from 1–3 h for ArI, 3–6 h for ArBr and 12–24 h for ArCl (Scheme 43). Good to excellent yields (65–98%) were reported. The catalyst could be recovered by centrifugation and, in studies of the coupling of PhI with indole, was found to be reusable five times with marginal loss of activity. The filtrate from the reaction was found to be inactive, Veisi et al. have used multi-walled carbon nanotubes to which thiosemicarbazide has been grafted to form supported Cu(I) complexes that are able to catalyse the Ullmann coupling of indole, amines or imidazoles with aryl halides [151]. The coupling reactions were optimally carried out in DMF/Et3N at 80 ◦C using a substrate:Cu ratio of 50/1 and reaction times ranging from 1–3 h for ArI, 3–6 h for ArBr and 12–24 h for ArCl (Scheme 43). Good to excellent yields (65–98%) were reported. The catalyst could be recovered by centrifugation and, in studies of the coupling of PhI with indole, was found to be reusable five times with marginal loss of activity. The filtrate from the reaction was found to be inactive, indicating that no leaching of active complex from the supported complexes had occurred. Veisi et al*.* have used multi-walled carbon nanotubes to which thiosemicarbazide has been grafted to form supported Cu(I) complexes that are able to catalyse the Ullmann coupling of indole, amines or imidazoles with aryl halides [151]. The coupling reactions were optimally carried out in DMF/Et3N at 80 °C using a substrate:Cu ratio of 50/1 and reaction times ranging from 1–3 h for ArI, 3–6 h for ArBr and 12–24 h for ArCl (Scheme 43). Good to excellent yields (65–98%) were reported. The catalyst could be recovered by centrifugation and, in studies of the coupling of PhI with indole, was found to be reusable five times with marginal loss of activity. The filtrate from the reaction was found to be inactive, indicating that no leaching of active complex from the supported complexes had occurred.

$$\text{Ar-X} + \text{ } \mathsf{Het-NH} \xrightarrow[\begin{subarray}{c} \mathsf{Et-NH} \\ \mathsf{Et}\_3 \mathsf{N}, \mathsf{DMF}, \ \mathsf{80} \ \mathsf{°C} \end{subarray}} \xleftarrow{\begin{subarray}{c} \mathsf{t} \mathsf{h} \mathsf{össemicarbzide-MWCNTS-Cu}^{\mathsf{I}} \end{subarray}} \mathsf{Ar-N-\mathsf{Het}}$$

indicating that no leaching of active complex from the supported complexes had occurred.

**Scheme 43.** Ulmann coupling of indole, amines, or imidazoles with aryl halides catalysed by **Scheme 43.** Ulmann coupling of indole, amines, or imidazoles with aryl halides catalysed by thiosemicarbazide‐multi-walled carbon nanotubes‐Cu<sup>I</sup> nanocatalyst. **Scheme 43.** Ulmann coupling of indole, amines, or imidazoles with aryl halides catalysed by thiosemicarbazide-multi-walled carbon nanotubes-Cu<sup>I</sup> nanocatalyst.

thiosemicarbazide‐multi-walled carbon nanotubes‐Cu<sup>I</sup> nanocatalyst. Halloysite is a form of natural clay that can be modified by the attachment of a variety of functionalities. Sadjadi has reported the conjugation of tosylated cyclodextrin to thiosemicarbazide functionalized halloysite, which in turn was used to immobilize Pd nanoparticles [152]. This immobilized system was then examined for its activity in the Sonogashira and Mizoroki–Heck Halloysite is a form of natural clay that can be modified by the attachment of a variety of functionalities. Sadjadi has reported the conjugation of tosylated cyclodextrin to thiosemicarbazide functionalized halloysite, which in turn was used to immobilize Pd nanoparticles [152]. This immobilized system was then examined for its activity in the Sonogashira and Mizoroki–Heck reactions. In the former case, a range of aryl halides were coupled with phenylacetylene or propargyl Halloysite is a form of natural clay that can be modified by the attachment of a variety of functionalities. Sadjadi has reported the conjugation of tosylated cyclodextrin to thiosemicarbazide functionalized halloysite, which in turn was used to immobilize Pd nanoparticles [152]. This immobilized system was then examined for its activity in the Sonogashira and Mizoroki–Heck reactions. In the former case, a range of aryl halides were coupled with phenylacetylene or propargyl

alcohol in water/EtOH at 60 ◦C, in the presence of K2CO<sup>3</sup> using 6 mol% Pd catalyst loading (Scheme 44). The activities followed the usual trend with iodides requiring the shortest reaction times (1.5–3.5 h) and giving the best conversions (83–95%) and chlorides requiring the longest reaction times (*ca.* 5 h) and giving moderate conversions (*ca.* 50%). In an examination of the recyclability of the catalyst, it was recovered and reused thirteen times in a typical reaction. The first four runs showed comparable activity but subsequent runs showed a gradual reduction such that from an original 95% conversion the final run gave 69%. In order to obtain more insight into the nature of the catalyst, the authors examined the recycled material by SEM, TEM and FT-IR. They found that there were no major observable differences after four cycles but thereafter there were indications of morphological changes due to agglomeration although the basic structure of the material was maintained. This agglomeration together with a limited amount of leaching that was also detected was presumed to be the cause of the gradual decrease in activity. The immobilised system was also demonstrated to be an active catalyst for the Mizoroki–Heck coupling of iodobenzene with styrene but a systematic examination of the scope of the reaction was not performed. Halloysite has also been functionalized with (3-chloropropyl) trimethoxysilane and subsequently reacted with thiosemicarbazide and furfural and then with Cu(OAc)<sup>2</sup> to provide an immobilized copper species [153]. Using ultrasonic irradiation, this system was active in the A3 coupling reactions of aldehydes, phenyl acetylene, and amines for synthesis of corresponding propargylamines. Very good conversions were obtained at room temperature within 30 min. The catalyst was readily recovered and after four runs showed little loss in activity. No leaching was detected and the catalyst reclaimed after successive runs and examination by FTIR, TEM, XRD, SEM, and EDX indicated it to be essentially unchanged. 44). The activities followed the usual trend with iodides requiring the shortest reaction times (1.5–3.5 h) and giving the best conversions (83–95%) and chlorides requiring the longest reaction times (*ca.* 5 h) and giving moderate conversions (*ca.* 50%). In an examination of the recyclability of the catalyst, it was recovered and reused thirteen times in a typical reaction. The first four runs showed comparable activity but subsequent runs showed a gradual reduction such that from an original 95% conversion the final run gave 69%. In order to obtain more insight into the nature of the catalyst, the authors examined the recycled material by SEM, TEM and FT-IR. They found that there were no major observable differences after four cycles but thereafter there were indications of morphological changes due to agglomeration although the basic structure of the material was maintained. This agglomeration together with a limited amount of leaching that was also detected was presumed to be the cause of the gradual decrease in activity. The immobilised system was also demonstrated to be an active catalyst for the Mizoroki–Heck coupling of iodobenzene with styrene but a systematic examination of the scope of the reaction was not performed. Halloysite has also been functionalized with (3-chloropropyl) trimethoxysilane and subsequently reacted with thiosemicarbazide and furfural and then with Cu(OAc)<sup>2</sup> to provide an immobilized copper species [153]. Using ultrasonic irradiation, this system was active in the A3 coupling reactions of aldehydes, phenyl acetylene, and amines for synthesis of corresponding propargylamines. Very good conversions were obtained at room temperature within 30 min. The catalyst was readily recovered and after four runs showed little loss in activity. No leaching was detected and the catalyst reclaimed after successive runs and examination by FTIR, TEM, XRD, SEM, and EDX indicated it to be essentially unchanged.

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 32 of 42

**Scheme 44.** Sonogashira reaction of aryl halides with terminal alkynes catalysed by Pd nanoparticles immobilized on tosylated cyclodextrin-thiosemicarbazide‐functionalized-halloysite nanotubes (Pd@HNTs‐T‐CD). **Scheme 44.** Sonogashira reaction of aryl halides with terminal alkynes catalysed by Pd nanoparticles immobilized on tosylated cyclodextrin-thiosemicarbazide-functionalized-halloysite nanotubes (Pd@HNTs-T-CD).

Finally, there have recently been reports on the use of thiosemicarbazide modified mesoporous silica materials in the immobilization of potential catalysts. Sadjadi et al*.* have prepared such a system, which consists of furfural thiosemicarbazone tethered through the terminal nitrogen to the mesoporous SBA-15 [154]. Reaction with copper acetate produced a system which, similar to that described above, was an active A3 coupling catalyst at ambient temperatures. Using a catalyst loading of 0.5 mol%, and under solvent-free conditions, very good yields of products, TONs of up to 190, and TOFs of up to 13 min–<sup>1</sup> were obtained within 40 min or less for the coupling of a variety of aryl aldehydes, phenyl acetylene, and morpholine or piperidine (Scheme 45). The reusability of the catalyst was also confirmed for four cycles. A similar copper system derived from the mesoporous material SBA-16 was used for C–S arylation reactions as reported by Ghodsinia et al*.* [155]. Coupling of aryl halides with elemental sulfur or thiourea provide symmetrical diaryl sulfides in generally very good yields. A catalyst loading of 1.3 mol% was used under solvent-free conditions in the presence of KOH. The yields in the reaction increased according to the aryl halide, ArX used, in the order Cl < Br < I. A study of the reusability of the catalyst indicated only a gradual loss of activity after seven runs. An array of techniques were employed to investigate the catalyst and it was found that the structural integrity of the material was maintained after successive runs. In addition, no significant leaching was detected. It was suggested that the loss of activity that had been observed was due to the partial saturation during the reaction process of the mesochannels containing the catalytic active sites. A very recent paper by Ahmadi et al*.* describes a magnetic mesoporous silica-Finally, there have recently been reports on the use of thiosemicarbazide modified mesoporous silica materials in the immobilization of potential catalysts. Sadjadi et al. have prepared such a system, which consists of furfural thiosemicarbazone tethered through the terminal nitrogen to the mesoporous SBA-15 [154]. Reaction with copper acetate produced a system which, similar to that described above, was an active A3 coupling catalyst at ambient temperatures. Using a catalyst loading of 0.5 mol%, and under solvent-free conditions, very good yields of products, TONs of up to 190, and TOFs of up to 13 min–1 were obtained within 40 min or less for the coupling of a variety of aryl aldehydes, phenyl acetylene, and morpholine or piperidine (Scheme 45). The reusability of the catalyst was also confirmed for four cycles. A similar copper system derived from the mesoporous material SBA-16 was used for C–S arylation reactions as reported by Ghodsinia et al. [155]. Coupling of aryl halides with elemental sulfur or thiourea provide symmetrical diaryl sulfides in generally very good yields. A catalyst loading of 1.3 mol% was used under solvent-free conditions in the presence of KOH. The yields in the reaction increased according to the aryl halide, ArX used, in the order Cl < Br < I. A study of the reusability of the catalyst indicated only a gradual loss of activity after seven runs. An array of techniques were employed to investigate the catalyst and it was found that the structural integrity of the material was maintained after successive runs. In addition, no significant leaching was detected. It was suggested that the loss of activity that had been observed was due to the partial saturation during the reaction process of the mesochannels containing the catalytic active sites. A very recent paper by Ahmadi et al. describes a magnetic mesoporous silica-Fe3O<sup>4</sup> nanocomposite

functionalised with a Pd thiosemicarbazone complex [156]. The material was investigated for its catalytic activity in the Suzuki–Miyaura reaction. Optimal conditions were found to be DMF as solvent and a temperature of 120 ◦C. The preferred base was K2CO<sup>3</sup> (1.2 mmol) and a 0.18 mol% (based on Pd) catalyst loading was used. A variety of aryl halides were examined in the reaction with phenyl boronic acid. With the exception of the hindered ortho-bromotoluene, all the halides used gave very good to excellent yields in short reaction times (60 min or less). After the catalytic run, the catalyst could be extracted using an external magnet. After washing and drying, the catalyst was reused and it was shown that it could be recycled for five times without significant decrease in the catalytic activity. Leaching was negligible and FT-IR and XRD indicated the structure of the catalyst to be unchanged after each cycle. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 33 of 42 to be DMF as solvent and a temperature of 120 °C. The preferred base was K2CO<sup>3</sup> (1.2 mmol) and a 0.18 mol% (based on Pd) catalyst loading was used. A variety of aryl halides were examined in the reaction with phenyl boronic acid. With the exception of the hindered ortho-bromotoluene, all the halides used gave very good to excellent yields in short reaction times (60 min or less). After the catalytic run, the catalyst could be extracted using an external magnet. After washing and drying, the catalyst was reused and it was shown that it could be recycled for five times without significant decrease in the catalytic activity. Leaching was negligible and FT-IR and XRD indicated the structure of the catalyst to be unchanged after each cycle.

$$\begin{array}{c} \stackrel{\text{O}}{\underset{\text{H}^{2}}{\overset{\text{O}}{\rightleftharpoons}}}\_{\text{H}^{2}} \stackrel{\text{H}}{\underset{\text{H}^{2}}{\overset{\text{-}}{\text{-}}}}\_{\text{H}^{2}} \stackrel{\text{N}}{\underset{\text{-}}{\text{-}}}\_{\text{R}} + \stackrel{\text{O}}{\underset{\text{H}^{2}}{\overset{\text{-}}{\text{-}}}}\_{\text{H}^{2}} \stackrel{\text{R}^{4}}{\underset{\text{solv\text{-}}}{\text{-}}}\_{\text{Sol\text{-}\text{-}\text{-}\text{S}}\text{H}^{2}} \stackrel{\text{R}^{3}}{\underset{\text{Sol\text{-}}}{\text{-}}}\_{\text{R}^{4}} \stackrel{\text{R}^{2}}{\underset{\text{H}^{2}}{\overset{\text{-}}{\text{-}}}}\_{\text{R}^{4}} \stackrel{\text{R}^{2}}{\underset{\text{H}^{2}}{\overset{\text{-}}{\text{-}}}}\_{\text{R}^{4}} \stackrel{\text{R}^{4}}{\underset{\text{R}^{4}}{\overset{\text{-}}{\text{-}}}}\_{\text{R}^{4}} \stackrel{\text{R}^{2}}{\underset{\text{R}^{2}}{\overset{\text{-}}{\text{-}}}}\_{\text{R}^{4}} \stackrel{\text{R}^{2}}{\underset{\text{R}^{2}}{\overset{\text{-}}{\text{-}}}}\_{\text{R}^{4}} \stackrel{\text{R}^{2}}{\underset{\text{R}^{2}}{\overset{\text{-}}{\text{-}}}}\_{\text{R}^{4}} \stackrel{\text{R}^{2}}{\underset{\text{R}^{2}}{\overset{\text{-}}{\text{-}}}}\_{\text{R}^{4}} \stackrel{\text{R}^{2}}$$

**Scheme 45.** A3 coupling reaction for the synthesis of propargylamines catalysed by Cu species immobilized on functionalized mesoporous SBA-15 with thiosemicarbazide and furfural (Cu@Fur-SBA-15). **Scheme 45.** A3 coupling reaction for the synthesis of propargylamines catalysed by Cu species immobilized on functionalized mesoporous SBA-15 with thiosemicarbazide and furfural (Cu@Fur-SBA-15).

#### **5. Future Prospects 5. Future Prospects**

It is clear that thiosemicarbazone complexes are promising catalysts for a number of applications. Phosphane-free thiosemicarbazone complexes as well as the analogous complexes with additional *P*-ligands as catalysts for cross-coupling reactions have received much attention during the last fifteen years. The fact that the ligands are relatively readily accessible and that the complexes formed show good stability make them popular subjects for investigation. Up until now, there have been relatively few reports concerning the nature of the species formed during the reactions using these complexes. More research into aspects such as the formation of nanoparticles, aggregation and deaggregation phenomena, leaching effects, the role of the ligands with different metals etc. is needed for the development of systems with general applicability. Undoubtedly, there will be increasing attention paid to areas such as catalyst immobilisation and to complexes that are active under mild, preferably aerobic conditions. The potential for applying these complexes in solvent-free or aqueous systems is also clear. An additional area where developments may be expected is that of asymmetric catalysis. Up until now there appear to be no reports of thiosemicarbazone complexes having been investigated for this purpose but chiral thiosemicarbazone ligands have certainly been prepared and it remains to be seen whether their complexes can show the appropriate selectivity. It is clear that thiosemicarbazone complexes are promising catalysts for a number of applications. Phosphane-free thiosemicarbazone complexes as well as the analogous complexes with additional *P*-ligands as catalysts for cross-coupling reactions have received much attention during the last fifteen years. The fact that the ligands are relatively readily accessible and that the complexes formed show good stability make them popular subjects for investigation. Up until now, there have been relatively few reports concerning the nature of the species formed during the reactions using these complexes. More research into aspects such as the formation of nanoparticles, aggregation and deaggregation phenomena, leaching effects, the role of the ligands with different metals etc. is needed for the development of systems with general applicability. Undoubtedly, there will be increasing attention paid to areas such as catalyst immobilisation and to complexes that are active under mild, preferably aerobic conditions. The potential for applying these complexes in solvent-free or aqueous systems is also clear. An additional area where developments may be expected is that of asymmetric catalysis. Up until now there appear to be no reports of thiosemicarbazone complexes having been investigated for this purpose but chiral thiosemicarbazone ligands have certainly been prepared and it remains to be seen whether their complexes can show the appropriate selectivity.

**Author Contributions:** I.D.K. and B.R.S. contributed equally. Conceptualization, I.D.K. and B.R.S.; writing original draft preparation, I.D.K. and B.R.S.; writing—review and editing, I.D.K. and B.R.S. All authors have **Author Contributions:** I.D.K. and B.R.S. contributed equally. Conceptualization, I.D.K. and B.R.S.; writing—original draft preparation, I.D.K. and B.R.S.; writing—review and editing, I.D.K. and B.R.S. All authors have read and agreed to the published version of the manuscript.

read and agreed to the published version of the manuscript. **Funding:** This research received no external funding.

**Funding:** This research received no external funding. **Conflicts of Interest:** The authors declare no conflict of interest.

**2019**, *385*, 137–173, doi:10.1016/j.ccr.2019.01.012.

advances in metal-catalyzed alkyl–boron (C(sp<sup>3</sup>

*10*, 296, doi:10.3390/catal10030296.

#### **Conflicts of Interest:** The authors declare no conflict of interest. **References**


)) Suzuki-Miyaura cross-couplings. *Catalysts* **2020**,


© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
